Virological and Social Outcomes of HIV-Infected Adolescents and Young Adults in The Netherlands Before and After Transition to Adult Care.

BACKGROUND: As a result of effective combination antiretroviral therapy (cART) and advanced supportive healthcare, a growing number of human immunodeficiency virus (HIV)-infected children survive into adulthood. The period of transition to adult care is often associated with impaired adherence to treatment and discontinuity of care. We aimed to evaluate virological and social outcomes of HIV-infected adolescents and young adults (AYAs) before and after transition, and explore which factors are associated with virological failure. METHODS: We included 59 HIV-infected AYAs from the Netherlands who had entered into pediatric care and transitioned from pediatric to adult healthcare. We used HIV RNA load and cART data from the Dutch Stichting HIV Monitoring database (1996-2014), and collected social and treatment data from patients' medical records from all Dutch pediatric HIV treatment centers and 14 Dutch adult treatment centers involved. We evaluated risk factors for virological failure (VF) in a logistic regression model adjusted for repeated measurements. RESULTS: HIV VF occurred frequently during the study period (14%-36%). During the transition period (from 18 to 19 years of age) there was a significant increase in VF compared with the reference group of children aged 12-13 years (odds ratio, 4.26 [95% confidence interval, 1.12-16.28]; P = .03). Characteristics significantly associated with VF were low educational attainment and lack of autonomy regarding medication adherence at transition. CONCLUSIONS: HIV-infected AYAs are vulnerable to VF, especially during the transition period. Identification of HIV-infected adolescents at high risk for VF might help to improve treatment success in this group.

Risk factors in an HIV-infected population for refraining from specialist care.

BACKGROUND: To obtain maximal benefit of combination antiretroviral therapy (cART), HIV-infected patients should be retained in medical care. Missed clinical visits are independently associated with all-cause mortality among HIV-infected patients. Our objective was to identify risk factors and patient-reported reasons for nonattendance at outpatient clinic appointments. DESIGN AND METHODS: We conducted a cross-sectional case-control study among 447 HIV-infected patients attending the outpatient clinic between March and July 2014. Patients with missed appointments from January 2013 onwards were included as cases and compared to a random selection of same-day controls without missed appointments during the same period. Clinical and socio-demographic characteristics were collected from clinical records and an interviewer-administered questionnaire. Additionally, reasons for nonattendance and possible solutions for future better attendance were addressed in the questionnaire. Multivariable logistic regression analysis was used to determine independent risk factors for nonattendance. RESULTS: A total of 224 cases and 223 controls were included. Independent risk factors for nonattendance were: (i) age <30 years (odds ratio (OR) 7.2; 95% CI: 3.2-16.3 versus ≥50 years); (ii) African region of origin (OR 2.8; 95% CI: 1.5-5.0 versus Western origin); (iii) having children <12 years of age (OR 2.1; 95% CI: 1.1-4.1); (iv) history of drugs- or alcohol abuse (OR 4.4; 95% CI: 1.8-10.8); (v) no cART (OR 2.5; 95% CI: 1.1-5.3) or HIV-RNA >400 copies/ml while receiving cART (OR 3.5; 95% CI: 1.3-9.6). The main reason given for nonattendance was failure to remember the appointments (44%). Most patients would prefer to receive an appointment reminder by SMS (80% of the cases and 55% of the controls). CONCLUSION: Missing outpatient clinic appointments were associated with available clinical characteristics. Nonattendance may be prevented by sending routine SMS reminders prior to the next appointment.

Efficacy of tenofovir and efavirenz in combination with lamivudine or emtricitabine in antiretroviral-naive patients in Europe.

BACKGROUND: The combination of tenofovir and efavirenz with either lamivudine or emtricitabine (TELE) has proved to be highly effective in clinical trials for first-line treatment of HIV-1 infection. However, limited data are available on its efficacy in routine clinical practice. METHODS: A multicentre cohort study was performed in therapy-naive patients initiating ART with TELE before July 2009. Efficacy was studied using ITT (missing or switch = failure) and on-treatment (OT) analyses. Genotypic susceptibility scores (GSSs) were determined using the Stanford HIVdb algorithm. RESULTS: Efficacy analysis of 1608 patients showed virological suppression to <50 copies/mL at 48 weeks in 91.5% (OT) and 70.6% (ITT). Almost a quarter of all patients (22.9%) had discontinued TELE at week 48, mainly due to CNS toxicity. Virological failure within 48 weeks was rarely observed (3.3%, n = 53). In multilevel, multivariate analysis, infection with subtype B (P = 0.011), baseline CD4 count <200 cells/mm³ (P < 0.001), GSS <3 (P = 0.002) and use of lamivudine (P < 0.001) were associated with a higher risk of virological failure. After exclusion of patients using co-formulated compounds, virological failure was still more often observed with lamivudine. Following virological failure, three-quarters of patients switched to a PI-based regimen with GSS <3. After 1 year of second-line therapy, viral load was suppressed to <50 copies/mL in 73.5% (OT). CONCLUSIONS: In clinical practice, treatment failure on TELE regimens is relatively frequent due to toxicity. Virological failure is rare and more often observed with lamivudine than with emtricitabine. Following virological failure on TELE, PI-based second-line therapy was often successful despite GSS <3.

Deep sequencing does not reveal additional transmitted mutations in patients diagnosed with HIV-1 variants with single nucleoside reverse transcriptase inhibitor resistance mutations.

OBJECTIVES: The aim of the study was to gain more insight into the relationship between transmitted singletons found at HIV diagnosis by population sequencing and the possible presence of clinically relevant viral minorities containing additional resistance mutations. METHODS: We studied the viral quasispecies and therapy response in 10 individuals with transmitted single nucleoside reverse transcriptase inhibitor (NRTI)-related resistance mutations as detected by population sequencing. RESULTS: Ultra-deep pyrosequencing did not reveal additional drug-resistance mutations in nine of 10 patients. In these nine patients, no breakthrough with resistant viruses was observed despite the use of low genetic nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens in the majority of patients. CONCLUSIONS: These data suggest that viral minority variants containing additional resistance mutations may be rare in patients with transmitted NRTI singletons in the Netherlands. Larger studies are required to confirm these findings and to determine the therapeutic consequences.

Use of highly active antiretroviral therapy is associated with lower prevalence of anal intraepithelial neoplastic lesions and lower prevalence of human papillomavirus in HIV-infected men who have sex with men.

BACKGROUND: The incidence of anal intraepithelial neoplasia (AIN) and anal cancer is increased in HIV-positive men who have sex with men (MSM). Persistent high-risk human papillomavirus (HPV) infection is an important etiologic agent. METHODS: In this study, a group of 250 HIV-positive MSM was included to determine the prevalence of AIN and to investigate the role of highly active antiretroviral therapy (HAART), high-risk HPV, and other risk factors possibly associated with this prevalence. RESULTS: Among patients included, 108 (43.2%) had lesions suspicious for AIN. Histologic analyses showed AIN 1 in 24 patients (22.2%), AIN 2 in 6 patients (5.6%), and AIN 3 in 10 patients (9.3%). In multivariable analyses, the use of HAART was associated with the absence of AIN (P = 0.045). In MSM without HAART, HPV infection was detected significantly more often compared with those who used HAART (P = 0.010). AIN was associated with HPV types 16 and 6. CONCLUSIONS: In this cross-sectional study in 250 HIV-positive MSM, the use of HAART was associated with lower prevalence of AIN and a significantly lower prevalence of HPV. This association between the prevalence of AIN and the absence of HAART may contribute to the current debate on when to start HAART in HIV-infected individuals.

Fendrix® compared to Engerix® in HIV-infected patients nonresponding to initial- and re-vaccination schedule.

BACKGROUND: In HIV-infected patients, the immunogenicity of hepatitis B vaccines is impaired. In this randomised controlled study (RCT), we investigated the effect of Fendrix® versus double-dose Engerix® vaccination in previously non-responsive HIV-infected subjects. METHODS: Patients included those who were HIV-infected and non-responders to a primary (single-dose hepatitis B (HBV) vaccination) and a subsequent double-dose HBV revaccination schedule. Subjects were randomised 1:1 to receive Fendrix® (t = 0, 4, 8, 24 weeks) or double-dose Engerix® (t = 0, 4, 24 weeks) vaccinations. Primary efficacy, defined as anti-HBs response ≥ 10 IU/l, was evaluated at week 28 in both study arms. RESULTS: A subset of 48 patients non-responsive to HBV vaccination was selected, from a cohort of patients at our institution, who underwent HBV vaccination unsuccessfully either in a previous RCT or through standard care. The anti-HBs ≥ 10 IU/l response rate at week 28 in the Fendrix® arm and the Engerix® arm were 85.7% and 65.0%, respectively (p = 0.09). There was no significant difference between the two used vaccine types in the anti-HBs levels reached. In our institution, the overall response rate after initial standard-dose vaccination schedule and double-dose revaccination in our cohort was 75%. In this study, combining the effects of Fendrix and Engerix resulted in a 75% response rate in the 25% remaining non-responders on initial and double-dose revaccination series. This yielded an absolute 19% increase and an overall response to HBV vaccination in HIV-infected patients of around 94% in our cohort. CONCLUSION: These results together, suggest that continuing HBV vaccination in non-responders to a first course of single-dose vaccine and a double-dose revaccination scheme is worth the effort. No superiority of one of the investigated hepatitis B vaccines was shown in this cohort but an appropriate number of patients needed to achieve reliable answers was not achieved.

Plasma HCV-RNA decline in the first 48 h identifies hepatitis C virus mono-infected but not HCV/HIV-coinfected patients with an undetectable HCV viral load at week 4 of peginterferon-alfa-2a/ribavirin therapy.

During peginterferon-alfa-2a/ribavirin therapy, plasma hepatitis C virus (HCV)-RNA decreases with a rapid first phase and a slower second phase. We compared the viral load decrease and slope in the first 48 h in patients with a rapid viral response (RVR, i.e. HCV-RNA < 50 IU/mL at week 4) with patients not achieving an RVR. From 23 HCV-infected (14 mono-infected and nine HCV/HIV-coinfected) genotype 1 or 4 positive peginterferon-alfa-2a/ribavirin-treated patients, plasma HCV-RNA was determined at baseline, 48 h, weeks 1, 2, 4, 8, 12, 48 and 72. The HCV viral load decrease (Delta0-48), the slope (lambda(1)) and the efficiency factor (epsilon) were determined in the first 48 h after the start of therapy. Five (36%) HCV mono-infected patients and three (33%) HIV/HCV-coinfected patients achieved an RVR whereas six (43%) HCV mono-infected patients and five (56%) HIV/HCV-coinfected patients reached a sustained viral response (SVR). In contrast to HIV/HCV-coinfected patients, five HCV mono-infected patients with an RVR showed both a larger Delta0-48 and steeper lambda(1) (-1.77log(10) IU/mL +/- 0.66 and -2.04/day +/- 0.76) compared to nine non-RVR patients (-0.66log(10) IU/mL +/- 0.39; P = 0.019 and -0.76/day +/- 0.41; P = 0.019). When divided by SVR, a greater Delta0-48 and steeper lambda(1) were also seen in both HCV mono-infected and HIV/HCV-coinfected patients. Thus, in the first 48 h after the start of therapy, HCV mono-infected patients with an RVR have a larger viral load decrease, steeper viral slope and a higher efficiency factor as compared with non-RVR patients.

Baseline lipid levels rather than the presence of reported body shape changes determine the degree of improvement in lipid levels after switching to atazanavir.

PURPOSE: To study factors influencing lipid changes after switching to atazanavir (ATV) and the effectiveness of ATV in maintaining virus suppression. METHODS: Retrospective cohort study in patients with viral suppression, comparing patients switching to ATV with those continuing combination antiretroviral therapy (cART). Outcome measures were 48-week total (TC), high-density (HDL) and low-density lipoprotein (LDL) cholesterol, and triglycerides (TG) changes, stratified for dyslipidemia and lipodystrophy and virological failure (time to first of two consecutive detectable HIV RNA). RESULTS: 225 patients switched to ATV (193 [85.8%] RTV boosted), and 3120 continued cART. In patients with baseline TC >6.2 mmol/L, those switching had greater mean (95% CI) TC decreases compared to those continuing cART (-1.26 [-1.63 to -0.89] and -0.54 [-0.64 to -0.44] mmol/L, p = .002). Likewise greater TG changes were observed in patients with high (>2.3 mmol/L) baseline TG (-1.44 [-2.05 to -0.83] and -0.54 [-0.70 to -0.38] mmol/L, p = .002). Effects were seen irrespective of presence of lipodystrophy. Patients switching to ATV had virological failure more often (17/224 [7.8%]) than those continuing cART (73/3100 [2.4%], p < .0001). CONCLUSIONS: Patients with virological suppression, including those with lipodystrophy, may benefit from switching to ATV with lipid profile improvement, especially if baseline lipid levels are high. This should be balanced against a possible higher virological failure risk.

A longitudinal and cross-sectional study ofEpstein-Barr virus DNA load: a possible predictor of AIDS-related lymphoma in HIV-infected patients.

INTRODUCTION: HIV-infected patients are more than 100-fold greater at risk for developing malignant AIDS-related lymphoma (ARL) compared to the general population. Most ARLs are EBV related. The main purpose of this study was to investigate whether a high peak EBV DNA load in HIV-infected patients is predictive of ARL, including classical Hodgkin lymphoma. METHODS: From an ongoing prospective HIV positive cohort study, we conducted a case-control study between 2004 and 2016 among patients from whom at least one EBV DNA load in serum or plasma was available. We compared peak EBV DNA load between patients with (49 cases) and without ARL (156 controls). RESULTS: The geometric mean of the peak EBV DNA load measured before diagnosis of malignant lymphoma was 52,565 IU/mL in EBER-positive lymphoma patients vs. 127 IU/mL in controls (p < .001). Patients with EBV DNA loads >100,000 IU/mL have an increased risk for diagnosis of malignant lymphoma compared to patients with EBV DNA loads ≤100,000 IU/mL (adjusted OR 12.53; 95%CI: 4.08; 38.42). In the longitudinal study, including 13 patients with at least three left-over plasma samples available for retesting, measurements of EBV-DNA during the preceding 12 months proved to be of poor value for predicting subsequent lymphoma diagnosis. CONCLUSIONS: A EBV DNA load >100,000 IU/mL can be useful in clinical setting to accelerate time to diagnosis and treatment. EBV-DNA loads in samples taken during the preceding year of ARL diagnosis showed to be of poor predictive value.

Wild type and YMDD variant of hepatitis B virus: no difference in viral kinetics on lamivudine/tenofovir therapy in HIV-HBV co-infected patients.

Prolonged lamivudine therapy has been identified as the major risk for the development of resistance in HBV, with rates of 90% after 4 years of treatment. Tenofovir disoproxil fumarate showed activity against both wild type and lamivudine resistant HBV in HIV-HBV co-infected patients. In order to compare the efficacy of lamivudine/tenofovir treatment we investigated detailed HBV kinetics in 13 HIV-HBV co-infected patients with either wild type HBV or lamivudine resistant HBV. The viral strains in both patient groups showed a biphasic viral decline pattern. Only in the first phase of viral decay, which reflects the clearance rate of the free virus from plasma, there was a statistically significant response in favor of the wild type group. After the first phase we observed a similar viral decline till 24 weeks of both groups. This is reassuring for many pretreated co-infected patients harbouring mutant viruses.

Limited patient adherence to highly active antiretroviral therapy for HIV-1 infection in an observational cohort study.

BACKGROUND: Adherence to highly active antiretroviral therapy (HAART) for human immunodeficiency syndrome type 1 (HIV-1) infection is essential to sustain viral suppression and prevent drug resistance. We investigated adherence to HAART among patients in a clinical cohort study. METHODS: Patients receiving HAART had their plasma concentrations of protease inhibitors or nevirapine measured and completed a questionnaire on adherence. We determined the percentage of patients who reported taking all antiretroviral medication on time and according to dietary instructions in the past week. Drug exposure was compared between patients reporting deviation from their regimen and fully adherent patients. Among patients who received HAART for at least 24 weeks, we assessed the association between adherence and virologic outcome. RESULTS: A total of 224 of 261 eligible patients completed a questionnaire. Forty-seven percent reported taking all antiretroviral medication on time and according to dietary instructions. Patients who reported deviation from their regimen showed lower drug exposure compared with fully adherent patients (median concentration ratio, 0.81 vs 1.07; P =.001). Among those receiving HAART for at least 24 weeks, patients reporting deviation from their regimen were less likely to have plasma HIV-1 RNA levels below 500 copies/mL (adjusted odds ratio, 4.0; 95% confidence interval, 1.4-11.6) compared with fully adherent patients. CONCLUSIONS: Only half of the patients took all antiretroviral medication in accordance with time and dietary instructions in the preceding week. Deviation from the antiretroviral regimen was associated with decreased drug exposure and a decreased likelihood of having suppressed plasma HIV-1 RNA loads. Patient adherence should remain a prime concern in the management of HIV-1 infection.

[Anorectal malignancies and dysplasia in HIV-positive men who have sex with men]. / Anuscarcinoom en voorstadia hiervan bij HIV-positieve mannen die seks hebben met mannen.

Since the HIV epidemic, the incidence ofanorectal (pre)malignancies in men who have sex with men (MSM) is increasing. The incidence is likely to increase further in the coming years, given that HIV-positive MSM are living longer thanks to powerful antiretroviral treatment. Persistent human papillomavirus (HPV) infection is a major risk factor for the development of anal (pre)malignancies. Less is known about the natural history of anal intraepithelial neoplasia (AIN). Screening in HIV-positive and HIV-negative MSM for anorectal malignancies or dysplasia is cost-effective if the incidence is sufficiently high. Treatment options range from watchful waiting for asymptomatic grade-1 AIN to excision or radio(chemo)therapy for anorectal carcinoma. HPV vaccines are in development. Especially in HIV-positive MSM with anorectal complaints or genital warts in their medical history, one should consider these malignancies.

Low mother-to-child-transmission rate of Hepatitis C virus in cART treated HIV-1 infected mothers.

BACKGROUND: Maternal transmission is the most common cause of HCV infection in children. HIV co-infection and high levels of plasma HCV-RNA have been associated with increased HCV transmission rates. OBJECTIVES: We assessed the vertical HCV transmission rate in the HIV-HCV co-infected group of pregnant women on cART. STUDY DESIGN: We conducted a retrospective study in a Dutch cohort of HIV-positive pregnant women and their children. We identified co-infected mothers. Results of the HCV tests of the children were obtained. RESULTS: All 21 women were on cART at the time of delivery. We analyzed data of the 24 live-born children at risk for mother-to-child transmission (MTCT) of HCV between 1996 and 2009. HIV-RNA was <500 copies/ml during 18/24 [75%] deliveries, the median CD4(+) cell count was 419 cells/µl (290-768). There was no transmission of HIV. The median plasma HCV-RNA in our cohort of 23 non-transmitting deliveries in 21 women was 3.5×10E5 viral eq/ml (IQR 9.6×104-1.5×106veq/mL). One of 24 live-born children was found to be infected with HCV genotype 1. At the time of delivery the maternal plasma HIV-RNA was <50 copies/ml, the CD4(+) cell count was 160 cells/µl and maternal plasma HCV-RNA was 4.6×10E6 veq/ml. This amounted to a prevalence of HCV-MTCT of 4%. CONCLUSION: In this well-defined cohort of HIV-HCV co-infected pregnant women, all treated with cART during pregnancy, a modest rate of vertical HCV transmission was observed.

Risk Factors for Sexual Transmission of Hepatitis C Virus Among Human Immunodeficiency Virus-Infected Men Who Have Sex With Men: A Case-Control Study.

Background. Since 2000, incidence of sexually acquired hepatitis C virus (HCV)-infection has increased among human immunodeficiency virus (HIV)-infected men who have sex with men (MSM). To date, few case-control and cohort studies evaluating HCV transmission risk factors were conducted in this population, and most of these studies were initially designed to study HIV-related risk behavior and characteristics. Methods. From 2009 onwards, HIV-infected MSM with acute HCV infection and controls (HIV-monoinfected MSM) were prospectively included in the MOSAIC (MSM Observational Study of Acute Infection with hepatitis C) study at 5 large HIV outpatient clinics in the Netherlands. Written questionnaires were administered, covering sociodemographics, bloodborne risk factors for HCV infection, sexual behavior, and drug use. Clinical data were acquired through linkage with databases from the Dutch HIV Monitoring Foundation. For this study, determinants of HCV acquisition collected at the inclusion visit were analyzed using logistic regression. Results. Two hundred thirteen HIV-infected MSM (82 MSM with acute HCV infection and 131 MSM without) were included with a median age of 45.7 years (interquartile range [IQR], 41.0-52.2). Receptive unprotected anal intercourse (adjusted odds ratio [aOR], 5.01; 95% confidence interval [CI], 1.63-15.4), sharing sex toys (aOR, 3.62; 95% CI, 1.04-12.5), unprotected fisting (aOR, 2.57; 95% CI, 1.02-6.44), injecting drugs (aOR, 15.62; 95% CI, 1.27-192.6), sharing straws when snorting drugs (aOR, 3.40; 95% CI, 1.39-8.32), lower CD4 cell count (aOR, 1.75 per cubic root; 95% CI, 1.19-2.58), and recent diagnosis of ulcerative sexually transmitted infection (aOR, 4.82; 95% CI, 1.60-14.53) had significant effects on HCV acquisition. Conclusions. In this study, both sexual behavior and biological factors appear to independently increase the risk of HCV acquisition among HIV-infected MSM.

HIV-2 infection in 12 European residents: virus characteristics and disease progression.

OBJECTIVE: To assess the disease progression rate among 12 HIV-2-infected West European residents (nine of West African descent), compared with the disease progression rate among HIV-1-infected individuals of the same population, and the characteristics of the HIV-2 strains involved. METHODS: HIV-2-infected individuals were identified by commercially available serological assays, their clinical status and CD4+ cell counts were monitored, and HIV-2 was isolated from their peripheral blood mononuclear cells. T-cell-line tropism and syncytium-inducing capacities of the isolated viruses were determined and their phylogenetic relationships were analysed by comparing polymerase chain reaction-amplified nucleotide sequences of reverse transcriptase (RT) gene segments. RESULTS: Eight of the 12 HIV-2-infected individuals presented with progressive disease and one of them progressed from Centers for Disease Control and Prevention group A1 to A3 within 36 months after seroconversion. The ratios of asymptomatic versus symptomatic individuals among residents of the Rotterdam region of West African descent were 2:7 for HIV-2 and 8:9 for HIV-1-infected individuals. HIV-2 was isolated from six of the nine individuals with progressive disease. The time required for virus isolation correlated inversely with the individuals' CD4+ cell counts. Five of the HIV-2 isolates replicated in immortalized T-cell lines, and two isolates from patients with AIDS were syncytium-inducing. Five HIV-2 isolates from patients born in the Cape Verdian Isles grouped together within subtype A. The HIV-2 isolate from a patient of Ghanese origin belonged to subtype B. Mutations were identified in the RT genes from HIV-2 isolates of two zidovudine-treated patients, one of which has also been shown to be involved in zidovudine resistance in HIV-1. CONCLUSION: Disease progression in HIV-2 infection may be as rapid as in HIV-1. HIV-2 isolation and viral phenotype were related to disease status, and mutations identical to those observed in HIV-1 zidovudine resistance were observed in patients treated with zidovudine.

Cerebrospinal fluid HIV-1 RNA during treatment with ritonavir/saquinavir or ritonavir/saquinavir/stavudine.

OBJECTIVE: To assess the HIV-1-RNA response and drug concentrations in cerebrospinal fluid (CSF) and serum during treatment with saquinavir (SQV)/ritonavir (RTV) or SQV/RTV plus stavudine (d4T) in HIV-1 -infected patients. DESIGN: A multicentre, open-label, randomized controlled trial. METHODS: A total of 208 protease inhibitor (PI) and d4T-naive, HIV-1-infected patients were treated with RTV 400 mg twice daily and SQV 400 mg twice daily with or without d4T 40 mg twice daily. Intensification with reverse transcriptase inhibitors was allowed if serum HIV RNA remained above 400 copies/ml after 12 weeks. In 27 volunteers, CSF and serum HIV RNA were measured at baseline, weeks 12 and 48, using the Roche Amplicor and the ultrasensitive assay. In 22 patients, serum and CSF drug concentrations were determined at week 12. RESULTS: The median baseline serum and CSF HIV-RNA concentrations were 4.81 and 3.21 log10 copies/ml, respectively. A difference in the proportion of patients with a CSF HIV-RNA level below the limit of quantification (< LLQ) after 12 weeks was found: four out of 14 (RTV/SQV) versus 12 out of 13 (RTV/SQV/d4T) (P = 0.001). The same results were found using the ultrasensitive assay. Patients with a baseline HIV-RNA level < LLQ in CSF remained < LLQ, regardless of the treatment regimen. Treatment with RTV/SQV alone was the only independent predictor of a CSF HIV-RNA level > LLQ at week 12 in logistic regression analysis (P = 0.005). CSF RTV and SQV concentrations were < LLQ in most patients. CONCLUSION: RTV/SQV alone cannot suppress detectable CSF HIV-1-RNA levels to < LLQ after 12 weeks of treatment in the majority of patients. CSF drug concentrations of RTV and SQV < LLQ may explain the suboptimal antiretroviral effect in the CSF.

CD4 T cells remain the major source of HIV-1 during end stage disease.

OBJECTIVE: To assess the source of HIV-1 production in lymphoid tissue biopsies from HIV-infected patients, with no prior anti-retroviral protease inhibitor treatment, with a CD4 cell count > 150 x 10(6)/l (group I) or < 50 x 10(6)/l (group II), co-infected with Mycobacterium tuberculosis or Mycobacterium avium complex. DESIGN AND METHODS: Lymphoid tissue biopsies from 11 HIV-1-infected patients, taken for diagnostic purposes, were studied by HIV-1 RNA in situ hybridization and immunohistochemistry. RESULTS: Patients of group I showed well organized granulomas, in contrast with patients of group II, in which granuloma formation was absent. HIV-1 RNA-positive cells in group I patients were found mainly around the granulomas, whereas in group II HIV-1-producing cells were confined to areas with remaining intact lymphoid tissue. Despite the abundant presence of macrophages, the productively infected HIV-1-positive cells in both groups were almost exclusively CD4 T cells. CONCLUSION: In contrast with previously published data, CD4 T cells appear to remain the major source of HIV-1 production in end-stage disease.

Urological complaints in relation to indinavir plasma concentrations in HIV-infected patients.

OBJECTIVE: To assess the relationship between indinavir-associated urological complaints and indinavir plasma concentrations. DESIGN: Case series, comparing indinavir plasma concentrations in cases with average concentrations in a control group. METHODS: Patients taking 800 mg indinavir three times a day (tid), who presented with overt urological complaints (renal colic, flank pain or haematuria) were selected for the study. Plasma indinavir concentrations were measured by means of a standardized high performance liquid chromatography (HPLC) method. Plasma samples taken at 1.5-8 h after the last indinavir ingestion were included for evaluation. Results were compared with the full pharmacokinetic curves of indinavir plasma concentrations from a control group of 14 patients taking 800 mg indinavir tid without urological complaints, and were expressed as concentration ratios. A ratio of 1 indicated a plasma concentration equalling the average concentration in the control population at the same point in time after the ingestion of indinavir. RESULTS: Seventeen patients (five women) were enrolled and the indinavir concentrations of 15 patients could be evaluated. Fourteen (93%) patients had a concentration above the mean of the controls, 12 (80%) patients had a concentration above the upper 95% confidence limit, and one (7%) patient had a concentration below the lower 95% confidence limit. The mean indinavir concentration in patients with urological complaints (ratio range 0.55-11.49) was significantly higher than the average concentration and the upper 95% confidence limit of the control group (P < 0.05). The results could not be explained by differences in weight, sex or drug interactions. Two patients had chronic active hepatitis B infection. In six patients with indinavir concentrations above the upper 95% limit, indinavir was reduced to 600 mg tid. Upon repeat measurement after the dose adjustment, their indinavir plasma concentrations fell within the 95% confidence interval around the mean of the control population. All six patients remained asymptomatic and had viral loads of less than 500 copies per ml after a follow-up of 5-16 months. CONCLUSIONS: Urological complications occurring during indinavir treatment were associated with elevated indinavir plasma concentrations in 80% of patients in this study. Indinavir plasma concentrations should be monitored upon presentation of urological complaints, on the basis of which dose reductions may be applied if brief interruption and increased hydration are ineffective.

The effect of treatment intensification in HIV-infection: a study comparing treatment with ritonavir/saquinavir and ritonavir/saquinavir/stavudine. Prometheus Study Group.

OBJECTIVE: To evaluate the effect of treatment with ritonavir (RTV)/saquinavir (SQV)/6 stavudine (D4T) or RTV/SQV alone, with treatment intensification if needed, in protease inhibitor- and D4T-naïve HIV-1-infected individuals. DESIGN: Multicentre, open-label, randomized controlled trial. Two-hundred and eight patients were randomized to receive treatment with RTV 400 mg/SQV 400 mg twice daily or RTV 400 mg/SQV 400 mg/D4T 40 mg twice daily. Intensification of study medication with reverse transcriptase inhibitors was permitted if serum HIV-RNA remained > 400 copies/ml after 12 weeks of treatment. Follow-up of this study was 48 weeks. RESULTS: In a strict intention-to-treat analysis, counting all dropouts as virological failures, 63% [95% confidence interval (CI), 54-73%] of subjects in the RTV/SQV group (n = 104) reached a serum HIV-RNA < 400 copies/ml at week 48, as compared with 69% (95% CI, 60-78%) in the RTV/SQV/D4T group (n = 104; P = 0.379). In the on-treatment analysis these percentages were 88 and 91% respectively. Thirty-one patients intensified their study medication according to the protocol (28 in the RTV/SQV group, three in the RTV/SQV/D4T group). Thirty out of 31 (97%) patients had a serum HIV-RNA < 400 copies/ml at their last follow-up visit. Ten per cent of patients discontinued study medication due to adverse events. CONCLUSION: The concept of starting with a simple, potent regimen, that could be intensified if necessary, showed good virological results after 48 weeks in this study, comparable to starting with more drugs from the beginning. Longer follow-up is needed to determine the long-term efficacy of this treatment strategy.

A phase II safety and efficacy study of amprenavir in combination with zidovudine and lamivudine in HIV-infected patients with limited antiretroviral experience. Amprenavir PROAB2002 Study Team.

OBJECTIVE: To determine the safety and efficacy of amprenavir (APV) in combination with lamivudine (3TC) and zidovudine (ZDV). DESIGN: Multicenter, randomized, partially blinded trial. SETTING: Nine study sites in the United States and Europe. PATIENTS: A group of 84 HIV-infected subjects with no prior 3TC or protease inhibitor therapy experience, CD4 cell count > or = 150 x 10(6) cells/l, and plasma HIV RNA > 10000 copies/ml. INTERVENTIONS: 3TC/ZDV with one of three doses of APV (900, 1050, or 1200 mg) versus 3TC/ZDV with 1050 mg placebo. All medications were dosed twice daily. The 1050 mg placebo and the APV 1050 mg dose were administered blinded. After 12 weeks, APV 1050 mg was substituted for 1050 mg placebo in the control group and the blind was maintained. MAIN OUTCOME MEASURES: Reduction in plasma HIV RNA from baseline; proportion of subjects with plasma HIV RNA < 400 copies/ml; and an increase in CD4 cell count from baseline. RESULTS: During the initial 12-week study period, APV/3TC/ZDV-treated subjects had greater viral suppression than the group receiving two nucleosides. By 48 weeks, 89% of subjects in the group taking the highest APV dose (1200 mg) had plasma HIV RNA < 400 copies/ml while 42% of the 900 mg group and 60% of the 3TC/ZDV group (1050 mg APV added at week 12) had plasma HIV RNA < 400 copies/ml using an as-treated analysis. By 60 weeks, 86% of subjects in the APV 1200 mg group had plasma HIV RNA < 400 copies/ml in the as-treated analysis, while 25% (900 mg), 43% (1050 mg), and 20% (1200 mg) of subjects had viral load <400 copies/ml in a strict intent-to-treat analysis owing to treatment discontinuations. Median CD4 cell count increases at week 60 were highest for the three treatment groups who received APV throughout the study, by intent-to-treat and as-treated analyses. The most common adverse events considered to be possibly drug related were nausea, rash, oral paresthesia, diarrhea, and fatigue. CONCLUSIONS: Treatment with APV, dosed at 1200 mg twice daily in combination with 3TC/ZDV, resulted in sustained viral suppression. This combination represents a potent alternative initial antiretroviral regimen for protease inhibitor-naive individuals.