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Introduction.- In former research we showed that 19% of home living geriatric patients suffered from malnutrition. Fifty-one percent were at risk for malnutrition. Aim of this study is to define determinants related to malnutrition. Methods.- Cross-sectional data from 173 patients was obtained at first hospital visit. Nutritional status was assessed by means of the Mini Nutritional Assessment (MNA 23.5 indicative of satisfactory nutritional status). Possible determinants of malnutrition were categorized into somatic factors (medication use, co morbidity), social factors (children, marital status), psychological factors (Mini Mental State Examination [MMSE] and Geriatric Depression Scale [GDS]) and functional status (Activities of Daily Life (ADL) and Instrumental Activities of Daily Life [IADL]). Both linear regression (with MNA as a dependent parameter) and logistic regression (MNA

Background The relationship between lopinavir plasma concentration and the magnitude of lipid elevation after initiation of lopinavir/ritonavir-containing antiretroviral therapy is unclear. The aim of this study was to determine the relationship between drug concentration and lipid changes in two patient cohorts. Methods First, we analysed, in an outpatient cohort, the correlation between percentage lipid changes and lopinavir concentration, measured at least 2 weeks or more after initiation of lopinavir/ritonavir. Second, we analysed the correlation between lipid changes and lopinavir and ritonavir plasma concentrations in antiretroviral-naive patients enrolled in a trial comparing nevirapine plus lopinavir/ritonavir (533/133 mg twice daily) with zidovudine/lamivudine plus lopinavir/ ritonavir (400/100 mg twice daily). Results In 82 outpatients with 215 lopinavir plasma measurements, we found no significant correlations between lopinavir concentration and changes in lipids a median of 522 days after lopinavir/ritonavir initiation in univariable regression analyses, nor in multivariable analyses adjusting for potential confounders. In 40 trial samples collected 24 months after treatment initiation, the mean (95% CI) percentage increase in low-density lipoprotein cholesterol (LDLc) was significantly greater in the nevirapine/ lopinavir/ritonavir group (29.4% [16.8–43.3]) than in the zidovudine/lamivudine/lopinavir/ritonavir group (6.8% [-7.3–23.1]; P=0.03). However, the percentage LDLc change did not correlate with lopinavir or ritonavir concentration ratios ( r=-0.25; P=0.17 and r=-0.06; P=0.75). Adding lopinavir or ritonavir concentrations into the multivariable regression analyses did not change the relation between LDLc change and randomized treatment. Conclusions Neither in an HIV outpatient clinic cohort nor in a trial comparing two lopinavir/ritonavir-containing therapies did we find any relation between changes in lipids, and lopinavir and ritonavir concentration, after initiating lopinavir/ritonavir-containing treatment.

OBJECTIVES: A possible mechanism for HIV therapy failure is the efflux of HIV drugs from viral target cells or certain body compartments by ATP-binding cassette (ABC) transporters, allowing ongoing viral replication. Here, we investigated the interaction between protease inhibitors (PIs) and ABC transporters. METHODS: To explore the potential blocking capacity of PIs, we exposed cells overexpressing multidrug resistance 1 P-glycoprotein (MDR1 P-gp), multidrug resistance protein 1 (MRP1) and breast cancer resistance protein (BCRP) to established cytotoxic substrates with or without one of the PIs atazanavir, lopinavir or ritonavir. Furthermore, to assess whether PIs serve as substrates, cell growth-inhibitory effects of these PIs were evaluated on cells overexpressing 1 of 11 ABC transporters and their parental counterparts. RESULTS: Atazanavir, lopinavir and ritonavir were highly effective in reversing resistance against established substrates in cells overexpressing MDR1 P-gp and MRP1, and, to a lesser extent, BCRP. Concurrently, however, PIs appeared to be relatively poor substrates for ABC transporters. Only a moderate level of resistance to atazanavir was observed in cells overexpressing MRP6 and MRP9 [resistance factor (RF): 2.0-2.6]. Cells overexpressing MDR1 P-gp, MRP3, MRP4 and MRP5 displayed low levels of resistance to atazanavir (RF: 1.3-1.7); MRP7- and MRP9-overexpressing cells to lopinavir (RF: 1.4-1.5); and MRP9-overexpressing cells to ritonavir (RF: 1.4). CONCLUSIONS: PIs can act as potent blockers of MDR1 P-gp, MRP1 and BCRP, but they are poor substrates for 11 ABC transporters. Consequently, ABC transporters are unlikely to play a major role in PI failure, but still may contribute to drug-specific adverse events and drug-drug interactions.

Direct detection of bacterial DNA in blood offers a fast alternative to blood culture and is presumably unaffected by the prior use of antibiotics. We evaluated the performance of two real-time PCR assays for the quantitative detection of Staphylococcus aureus bacteremia and for Enterococcus faecalis bacteremia directly in blood samples, without prior cultivation. Whole-blood samples for PCR were obtained simultaneously with blood cultures from patients admitted to the intensive care unit of our hospital. After the extraction of DNA from 200 μl of blood, real-time PCR was performed for the specific detection and quantification of S. aureus and E. faecalis DNA. The sensitivity for bacteremia of the S. aureus PCR was 75% and that of the E. faecalis PCR was 73%, and both tests had high specificity values (93 and 96%, respectively). PCR amplification reactions were positive for S. aureus for 10 (7%) blood samples with negative blood cultures, and 7 (4%) PCR reactions were positive for E. faecalis . The majority of these PCR results were likely (50%) or possibly (42%) related to infection with the specific microorganism, based on clinical data and radiological and microbiological investigations. PCR results were concordant for 95% of paired whole-blood samples, and blood culture results were concordant for 97% of the paired samples. We conclude that the detection of S. aureus and E. faecalis DNA in blood by real-time PCR enables a rapid diagnosis of bacteremia and that a positive DNAemia is related to proven or possible infection with the specific microorganism in the majority of patients with negative blood cultures.

Objective: To compare changes in quality of life (QoL) over 96 weeks in patients enrolled in a triple-therapy protocol, a treatment-intensification protocol, or an induction-maintenance therapy protocol, and to compare QoL between patients who continued and discontinued their antiretroviral regimen. Patients: Naive patients enrolled in a triple-therapy protocol (zidovudine/lamivudine or stavudine/didanosine or stavudine/lamivudine supplemented with protease inhibitor therapy of choice) (n = 35), a protocol of treatment intensification (ritonavir/saquinavir or ritonavir/saquinavir/stavudine) (n = 74) in which therapy was intensified with nucleoside analogue(s) in cases of insufficient viral suppression, and a protocol of induction (saquinavir/nelfinavir/lamivudine/stavudine) maintenance (saquinavir/nelfinavir or stavudine/nelfinavir) therapy (n = 50). Main outcome measure: Changes from baseline in QoL assessed by the Medical Outcomes Study HIV Health Survey at weeks 0, 12, 24, 36, 48, 72 and 96. Results: Patients in the triple-therapy and treatment-intensification protocols showed more favourable changes in physical function, social function, mental health, energy/fatigue, health distress and overall QoL compared to patients in the induction-maintenance protocol, with patients in the first two protocols showing improvements in QoL and those in the induction-maintenance protocol showing declining or unchanged QoL. Patients who discontinued study medication due to insufficient efficacy, toxicities or at their own request showed less favourable changes in QoL compared with patients who continued their regimen. The highest proportion of discontinuations was within the induction-maintenance protocol. Conclusion: Antiretroviral treatment strategies that are effective and tolerable have the potential to improve patients' QoL over 96 weeks.

Background: Changes in body fat distribution are an adverse effect of therapy with HIV protease inhibitors (PI). It has been suggested that nucleoside analogue reverse transcriptase inhibitors (NRTI) may also contribute to this so-called lipodystrophy syndrome, but the relative contribution of the two drug classes is unclear as they are usually administered concomitantly. Method: The occurrence of lipodystrophy, as reported by physicians using no standardized criteria, was followed in patients randomly assigned to treatment with either a PI alone or a PI combined with an NRTI. The patients were part of a multicenter, open-label, randomized comparison of ritonavir (RTV)/saquinavir (SQV) with or without the addition of stavudine (d4T) in HIV-1-infected patients without prior PI and d4T experience (the Prometheus study). Results: Lipodystrophy was reported in 29 of 175 (17%) patients during 96 weeks of follow up. Overall, it was reported significantly more frequently in patients who were randomized to RTV/SQV/d4T (22/88; 25%), than in patients randomized to RTV/SQV alone (7/87; 8%) (P = 0.003). When the analysis was limited to patients without any prior antiretroviral experience, lipodystrophy likewise was significantly more frequent in patients randomized to RTV/SQV/d4T (12/50; 24%) than in those randomized to RTV/SQV (2/44; 5%) (P = 0.008). Conclusion: This randomized clinical trial, in spite of not having been blinded, supports a contributory role of NRTI in the development of antiretroviral therapy-associated lipodystrophy. The low incidence of lipodystrophy in patients with no or limited NRTI exposure supports further evaluation of NRTI-sparing regimens as alternatives to current antiretroviral regimens.

Diarrhoea in HIV-1 infected persons is an important clinical problem. To improve care and counselling, information about the way, and the extent to which, diarrhoea influences the daily life of these patients can be useful. A cross-sectional descriptive study was performed at the HIV infection clinic of three major hospitals in Amsterdam. A diary, the Coates card system (to determine the relative severity of the symptoms) and an interview were used as outcome measures. Sixty-two patients participated and were classified into four groups: group 1 (minor diarrhoea, n = 26), group 2 (mild diarrhoea, n = 18), group 3 (moderate diarrhoea, n = 7) and group 4 (severe diarrhoea, n = 11). Diarrhoea was considered a very severe symptom in groups 2, 3 and 4. Even mild diarrhoea may have a debilitating impact on the day-to-day life of HIV-infected patients. Faecal incontinence occurs frequently. Patients can worry about their diarrhoea because of lack of information. Patients who do not have diarrhoea according to current definitions of it, consider diarrhoea to be equally problematic as those with (moderate) diarrhoea. More information on prognosis and practical solutions for patients are recommended.

Objectives: Triple combination treatment of HIV-1 infection using two reverse transcriptase inhibitors and a protease inhibitor can result in significant and sustained decreases in the quantity of viral RNA in peripheral blood. Lymphoid tissue, however, constitutes the major reservoir of HIV in infected patients. Study of the viral burden in these tissues has provided additional insight in the efficacy of antiretroviral treatment. Design: Patients were randomized into two groups in order to study differences in the development of resistance to reverse transcriptase inhibitors. Group I started treatment with all three drugs simultaneously. Group II started with ritonavir monotherapy, aiming at initial reduction in virus production before the addition of lamivudine and zidovudine 3 weeks later. Methods: Changes in the amount of HIV in plasma and tonsillar lymphoid tissue during 24 weeks of treatment with ritonavir, lamivudine and zidovudine were studied by reverse transcriptase polymerase chain reaction. Results: Thirty-three antiretroviral-naive HIV-infected patients were included for analysis. After 24 weeks, median CD4+ cell count increased by 152 x 106/l and median plasma viral RNA levels decreased by at least 2.87 log10 copies/ml. In 88% of the patients remaining on treatment, plasma RNA levels were below the quantification limit of the assay used (mean, 2.4 log10 copies/ml). The lymphoid tissue viral burden, ranging from 9.16 to 8.52 log10 copies/g at baseline, was markedly reduced with at least 2.1 log10 copies/g by week 24 in the five patients analysed. Eight patients (24%) withdrew because of side-effects. In one patient in group II, ritonavir and lamivudine resistance-associated mutations developed. Conclusions: Treatment with this triple antiretroviral drug combination produced a durable and strong decrease of HIV-1 RNA burden in both plasma and lymphoid tissue.

summary Background & aims: Few data is available on the nutritional status of geriatric outpatients. The aim of this study is to describe the nutritional status and its clinical correlates of independently living geriatric older individuals visiting a geriatric outpatient department. Methods: From 2005 to 2010, all consecutive patients visiting a geriatric outpatient department in the Netherlands were screened for malnutrition. Nutritional status was assessed by the Mini Nutritional Assessment (MNA). Determinants of malnutrition were categorized into somatic factors (medicine use, comorbidity, walking aid, falls, urinary incontinence), psychological factors (GDS-15 depression scale, MMSE cognition scale), functional status (Activities of Daily Life (ADL), Instrumental ADL (IADL)), social factors (children, marital status), and life style factors (smoking, alcohol use). Univariate and multivariate logistic regression analyses, adjusted for age and sex and all other risk factors were performed to identify correlates of malnutrition (MNA < 17). Results: Included were 448 outpatients, mean (SD) age was 80 (7) years and 38% was men. Prevalence of malnutrition and risk for malnutrition were 17% and 58%. Depression, being IADL dependent, and smoking were independently associated with an increased risk of malnutrition with OR’s (95%CI) of 2.6 (1.3e5.3), 2.8 (1.3e6.4), 5.5 (1.9e16.4) respectively. Alcohol use was associated with a decreased risk (OR 0.4 (0.2e0.9)). Conclusion: Malnutrition is highly prevalent among geriatric outpatients and is independently associated with depressive symptoms, poor functional status, and life style factors. Our results emphasize the importance of integrating nutritional assessment within a comprehensive geriatric assessment. Future longitudinal studies should be performed to examine the effects of causal relationships and multifactorial interventions.

The objective of this study was to determine whether granzyme B- expressing cells, which identify activated cytotoxic lymphocytes, are present in the small intestinal mucosa of human immunodeficiency virus (HIV)-infected patients with and without diarrhea. Therefore, duodenal biopsy specimens from 29 HIV-infected patients (11 with diarrhea and 18 without diarrhea) and 15 control patients were stained for the presence of granzyme B expressing cells. In HIV-infected patients, a significantly increased expression of granzyme B in the lamina propria was observed (p = 0.00001): In 22 of 29 patients, at least 5-10 cells per high-power field were counted. In contrast, in 13 of 15 control patients, granzyme B was not expressed or minimally so, and in two others a maximum of five granzyme-B-expressing cells could be detected per high-power field. No significant difference was found between the HIV-infected patients with and without diarrhea. Double staining revealed that the granzyme-B-expressing cells were mainly CD3 positive. These data show that activated cytotoxic T lymphocytes (CTLs) are present in the duodenal mucosa of HIV-infected patients. No relation between the number of CTLs and the presence of diarrhea was demonstrated. CTLs are known to be involved in the pathogenesis of HIV infection and in the production of tissue injury, but their functional role in intestinal HIV-related pathology has yet to be elucidated.

Background: Falls occur frequently in older people and strongly affect quality of life. Guidelines recommend multifactorial, targeted fall prevention. We evaluated the effectiveness of a multifactorial intervention in older persons with a high risk of recurrent falls. Methods: A randomized controlled trial was conducted from April 3, 2005, to July 21, 2008, at the geriatric outpatient clinic of a university hospital and regional general practices in the Netherlands. Of 2015 persons identified, 217 persons aged 65 years or older were selected to participate. They had a high risk of recurrent falls and no cognitive impairment and had visited the emergency department or their family physician after a fall. The geriatric assessment and intervention were aimed at reduction of fall risk factors. Primary outcome measures were time to first and second falls after randomization. Secondary outcome measures were fractures, activities of daily living, quality of life, and physical performance. Results: Within 1 year, 55 (51.9%) of the 106 intervention participants and 62 (55.9%) of the 111 usual care (control) participants fell at least once. No significant treatment effect was demonstrated for the time to first fall (hazard ratio, 0.96; 95% confidence interval, 0.67-1.37) or the time to second fall (1.13; 0.71-1.80). Similar results were obtained for secondary outcome measures and for perprotocol analysis. One intervention participant died vs 7 in the control group (hazard ratio, 0.15; 95% confidence interval, 0.02-1.21). Conclusion: This multifactorial fall-prevention program does not reduce falls in high-risk, cognitively intact older persons. Trial Registration: isrctn.org Identifier: ISRCTN11546541. ©2010 American Medical Association. All rights reserved.

Objective: To determine the safety and pharmacokinetics of the nucleoside analogue, 3TC. Design: A Phase I, open-label, single-centre study. Methods: Twenty asymptomatic, HIV-infected male patients with CD4 lymphocyte counts 6/l who had not received previous antiretroviral therapy completed the study. Each patient received a single intravenous dose followed by a single oral dose of 3TC. Four patients were dosed at each of five dose levels (0.25,1.0, 2.0, 4.0 and 8.0 mg/kg). Results: The most commonly reported adverse event was headache, which was generally reported to be mild. The mean bioavailability of 3TC was 82% following oral administration. The majority of the dose (approximately 70%) was excreted unchanged in the urine. Conclusions: Overall, 3TC was well tolerated following dosing, and there were no significant changes in the safety parameters measured. Phase I/II clinical trials with 3TC are ongoing to evaluate its safety, pharmacokinetics and preliminary activity.

The irrational prescribing of drugs seems to be a general problem in medical practice, occasionally leading to serious consequences. In order to improve the drug prescribing performance of medical students, a compulsory context-learning pharmacotherapy module was implemented in 1998 in the medical curriculum of 2nd–4th-year medical students at the VU University Medical Center (VUmc), Amsterdam, the Netherlands. As part of this program, preclinical medical students are taught how to select, prescribe, and evaluate a drug regimen rationally. The aim of this study was to investigate the effect of this preclinical pharmacotherapy program on the quality of rational prescribing during the ensuing clinical clerkship of these students in internal medicine. The results of this study indicate that preclinical context-learning in pharmacotherapy leads to the use of more rational prescribing modalities by medical students during their ensuing clinical clerkship in internal medicine. This effect was obtained not only with respect to the clinical topics in which training had been given as part of the pharmacotherapy curriculum, but also for other disease situations that the students dealt with. This implies that students not only remember the specific information they have learned during the training, but are also able to apply the acquired skills in new situations (transfer effect). Clinical Pharmacology & Therapeutics (2008); 84, 4, 513–516 doi:10.1038/clpt.2008.82

We evaluated a modified fluorescence in situ hybridization (FISH) assay for rapid (

Objectives: Current research is unclear about the most effective pharmacological agents for managing the loss of weight and fat-free mass common in HIV/AIDS. The aim of this study was to compare nandrolone decanoate with placebo and testosterone. Methods: The study was a multicentre randomized double-blind placebo-controlled trial. Three hundred and three adult HIV-positive male patients with a weight loss of 5-15% in the last 12 months, or a body mass index of 17-19 kg/m2, or a body cell mass/height ratio lower than 13.5 kg/m, were randomly assigned to receive nandrolone decanoate (150 mg), testosterone (250 mg) or placebo intramuscularly every 2 weeks for 12 weeks. Fat-free mass, weigth, immune markers and perception of treatment were the main outcome measures. Results: Treatment with nandrolone resulted in significantly greater increases in fat-free mass [mean increase 1.34 kg; 95% confidence interval (CI) 0.60; 2.08 kg] and in weight (mean increase 1.48 kg; 95% CI 0.82; 2.14 kg) compared with placebo. The mean increase in weight with nandrolone of 1.00 kg (95% CI 0.27; 1.74 kg) when compared with testosterone was significant, although the difference in fat free mass did not reach significance (mean increase 0.69 kg; 95% CI-0.13; 1.51 kg). Patient perception of benefit was significantly greater in the nandrolone group when compared with both the placebo and the testosterone groups. Conclusion: Treatment with nandrolone decanoate increased body weight when compared with placebo and testosterone. Nandrolone decanoate treatment resulted in greater increases in fat-free mass than placebo and demonstrated a trend for a significant increase when compared with testosterone.

Rapid identification of microorganisms in blood cultures is required to optimize empirical treatment at an early stage. Fluorescence in situ hybridization (FISH) can reduce the time to identification of microorganisms in growth-positive blood cultures. In this study, we evaluated the performance, time to identification, and potential clinical benefits of FISH compared to those of conventional culture methods in routine practice. After Gram staining, blood culture fluids were simultaneously further identified with FISH and with conventional culture methods. Results and points in time of FISH and culture identification (provisional and final identifications) were collected and compared. For 91% of microorganisms, the genus or family name was identified, and for 79%, the species name could be attributed. The sensitivity and specificity of the individual probes exceeded 95%, except for the Enterobacteriaceae probe (sensitivity, 89%). Cross-hybridization was obtained with the Klebsiella pneumoniae probe for Klebsiella oxytoca . The time gains of FISH and final culture identification were more than 18 h for bacteria and 42 h for yeasts. With FISH, Staphylococcus aureus was differentiated from coagulase-negative staphylococci 1.4 h faster than by provisional identification ( P < 0.001). In conclusion, FISH allows rapid and reliable identification of the majority of microorganisms in growth-positive blood cultures. The substantial time gain of identification with FISH may allow same-day adjustment of antimicrobial therapy, and FISH is especially useful if no provisional identification is obtained. With further extension of the number of probes and a reduction in turnaround time, FISH will become a very useful diagnostic tool in the diagnosis of bloodstream infections.

New techniques have emerged for the detection of bacteria in blood, because the blood culture as gold standard is slow and insufficiently sensitive when the patient has previously received antibiotics or in the presence of fastidious organisms. DNA-based techniques, hybridisation probes, and PCR-based detection or protein-based detection by mass spectroscopy are aimed at rapid identification of bacteria and provide results within 2 h after the first signal of growth in conventional blood cultures. Also, detection of microorganisms directly in blood by pathogen-specific or broad-range PCR assays (eubacterial or panfungal) shows promising results. Interpretation is complex, however, because of detection of DNA rather than living pathogens, the risk of interfering contamination, the presence of background DNA in blood, and the lack of a gold standard. As these techniques are emerging, clinical value and cost-effectiveness have to be assessed. Nevertheless, molecular assays are expected eventually to replace the current conventional microbiological techniques for detection of bloodstream infections.

Contains fulltext : 186259.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To assess the clinical, immunological and virological response and the emergence of resistance towards antiretroviral therapy (ART) in a cohort of HIV-2-infected patients. DESIGN: Observational study. PATIENTS: HIV-2-infected patients residing in the Netherlands. RESULTS: From 1995 to 2001 seven patients failed various ART regimens. The resistance mutations were analysed retrospectively. Development of mutations proved to be similar to that observed in HIV-1-infected patients, with the exception of a higher occurrence of the Q151M mutation within the reverse transcriptase gene. In a prospective study, comprising 13 consecutive naive HIV-2-infected patients, all patients achieved plasma HIV-2-RNA suppression below the detection limit (500 copies/ml). The antiretroviral regimen consisted of two nucleoside reverse transcriptase inhibitors (NRTIs) and indinavir, with a boosting dose of ritonavir; the median follow-up was 91 weeks. Two patients experienced a temporary virological rebound, while at the same time therapeutic drug monitoring showed sub-therapeutic plasma levels of indinavir. CONCLUSION: Sustained viral suppression in HIV-2-infected patients can be achieved using an antiretroviral regimen of two NRTIs and boosted indinavir or lopinavir.

To evaluate the effect of treatment of HIV-1 infection with combination therapy consisting of since 1996 in the Netherlands available protease and reverse transcriptase inhibitors.Prospective cohort study.In an observational clinical cohort of HIV-1-infected individuals, the short-term successful treatment end point of antiviral therapy including at least one antiretroviral drug licensed in the Netherlands since July 1, 1996 (protease inhibitors and reverse transcriptase inhibitors), was HIV-1 RNA plasma levelsor = 500 copies/ml (virological success). Cox proportional hazard models were used to identify prognostic markers for therapy success. The study included 2,148 infected individuals with a median follow-up of 135 weeks of treatment; 1,049 had been pre-treated with antiretroviral drugs before starting their new regimen and 1,099 were treatment naive.Plasma HIV-1 RNA levelsor = 500 copies/ml at 24 weeks of treatment were seen in 61% of all patients. The chance of therapy success for naive patients was twice that for pre-treated patients (relative risk: 1.8; por = 0.001). Following the first 24 weeks, the chance of virological success was higher in the naive group (78% versus 63%; por = 0.001), and the number of naive patients failing therapy after initial success was smaller compared to pre-treated patients (22% versus 45%; por = 0.001). In the naive group, the CD4+ T-cell number increased from 239 to 440 (x 10(6) cells/l) in case of success, and decreased from 150 to 320 in case of treatment failure. HIV-1 related morbidity declined from 0.26 to 0.05 and mortality dropped from 0.07 to 0.03 per person-year of follow-up. Regimens were changed at least once in 76% of patients. Toxicity and therapy failure were the main reasons for regimen changes in naive and pre-treated patients, respectively.A combination of antiretroviral drugs, including at least one of the drugs licensed since 1996, led to a drop in HIV-1 plasma concentrations. Morbidity and mortality also decreased. The chance of a better immunological and virological response to the new drug regimens was greatest in therapy-naive patients.

In collaboration with the Dutch Institute for Health Care Improvement (CBO) and on the basis of recent developments, new guidelines have been developed for the diagnosis and treatment of HIV-infected patients. The most important recommendations are: Treatment of adult patients is indicated if HIV load30,000 RNA copies/ml, or when CD4+ cell count is350 x 10(6) cells/l. Treatment of children is indicated if HIV load5,000 copies/ml, even when CD4+ cell count is500 x 10(6) cells/l. Optimal antiretroviral treatment consists of a combination of two nucleoside reverse transcriptase inhibitors (NRTIs) and one protease inhibitor, or a combination of two NRTIs and one non-nucleoside reverse transcriptase inhibitor. Patients on antiretroviral treatment should be monitored every 3 months. Undetectable HIV load should be the target of first- or second-line antiretroviral treatment. In order to prevent HIV transmission from mother to child, prescription of antiretroviral drugs after the first three months of pregnancy is indicated in pregnant women with a detectable HIV load. Prophylaxis of opportunistic infections can be discontinued if CD4+ cell count recovers above 200 x 10(6)/l. In case of exposure to HIV due to a needle or other occupational accident or unsafe sexual contact, post-exposure prophylaxis should be offered after careful risk evaluation. Preferably, vaccination to prevent pneumococci infections, influenza, hepatitis A or hepatitis B should be given when CD4+ cell count is200 x 10(6)/l.

To evaluate the antiretroviral activity and safety of multiple escalating doses of amprenavir administered alone, and in combination with abacavir in HIV-1-infected adults.Sixty-two HIV-1-infected subjects were enrolled in a multicentre, open-label, non-randomized, dose-escalating trial.Subjects were assigned to one of six dose groups and received amprenavir 300 mg twice daily, 300 mg three times daily, 900, 1050, or 1,200 mg twice daily for 4 weeks. One dose group received amprenavir 900 mg twice daily in combination with abacavir 300 mg twice daily for 4 weeks. Antiretroviral activity was assessed by measuring changes from baseline in plasma HIV-1 RNA levels and CD4 cell counts. Safety was evaluated by monitoring clinical adverse events and changes in laboratory values. Genotypic and phenotypic analyses were performed using ABI sequencing and the recombinant virus assay, respectively.At week 4, amprenavir monotherapy (900, 1,050, or 1,200 mg twice daily) resulted in marked decreases in plasma HIV-1 RNA levels (1.3-1.6 log10 copies/ml), and substantial increases in CD4 cell counts in the two dose groups who received 1,050 mg twice daily (118 x 10(6) cells/mm3) or 1,200 mg twice daily (114 x 10(6) cells/mm3). Amprenavir/abacavir resulted in median plasma HIV-1 RNA reductions of 1.8 log10 copies/ml, and median CD4 cell count increases of 138 x 10(6) cells/mm3. Amprenavir was reasonably well tolerated with few treatment-limiting adverse events. No known active site mutations associated with amprenavir resistance were selected in any of the dose groups, and no significant phenotypic resistance to amprenavir developed during 4 weeks of therapy.The antiviral effect of amprenavir monotherapy increased with escalating doses, and all amprenavir doses were reasonably well tolerated over 4 weeks of therapy. Amprenavir/abacavir combination therapy elicited a potent antiviral effect. The three highest doses of amprenavir (900, 1,050 and 1,200 mg twice daily) were selected to design subsequent Phase II and III studies that confirmed the safety profile and efficacy of amprenavir in combination regimens and led to the approval of amprenavir in the USA in 1999.

Objective To evaluate the antiretroviral activity and safety of multiple escalating doses of amprenavir administered alone, and in combination with abacavir in HIV-1-infected adults. Design Sixty-two HIV-1-infected subjects were enrolled in a multicentre, open-label, non-randomized, dose-escalating trial. Methods Subjects were assigned to one of six dose groups and received amprenavir 300 mg twice daily, 300mg three times daily, 900, 1050, or 1200 mg twice daily for 4 weeks. One dose group received amprenavir 900 mg twice daily in combination with abacavir 300 mg twice daily for 4 weeks. Antiretroviral activity was assessed by measuring changes from baseline in plasma HIV-1 RNA levels and CD4 cell counts. Safety was evaluated by monitoring clinical adverse events and changes in laboratory values. Genotypic and phenotypic analyses were performed using ABI sequencing and the recombinant virus assay, respectively. Results At week 4, amprenavir monotherapy (900, 1050, or 1200 mg twice daily) resulted in marked decreases in plasma HIV-1 RNA levels (1.3–1.6 log10 copies/ml), and substantial increases in CD4 cell counts in the two dose groups who received 1050 mg twice daily (118x106 cells/mm3) or 1200 mg twice daily (114x106 cells/mm3). Amprenavir/abacavir resulted in median plasma HIV-1 RNA reductions of 1.8 log10 copies/ml, and median CD4 cell count increases of 138x106 cells/mm3. Amprenavir was reasonably well tolerated with few treatment-limiting adverse events. No known active site mutations associated with amprenavir resistance were selected in any of the dose groups, and no significant phenotypic resistance to amprenavir developed during 4 weeks of therapy. Conclusions The antiviral effect of amprenavir monotherapy increased with escalating doses, and all amprenavir doses were reasonably well tolerated over 4 weeks of therapy. Amprenavir/abacavir combination therapy elicited a potent antiviral effect. The three highest doses of amprenavir (900, 1050 and 1200 mg twice daily) were selected to design subsequent Phase II and III studies that confirmed the safety profile and efficacy of amprenavir in combination regimens and led to the approval of amprenavir in the USA in 1999.

We studied the intrahost evolution and dynamics of a multidrug-resistant HIV-1, which contains an insertion of two amino acids (aa) and several aa changes within the reverse transcriptase (RT) gene. From an individual receiving intermittent therapy, sequences of 231 full-length molecular clones of HIV-1 RT were obtained from serum-derived viruses at 12 consecutive time points over a period of 6 years, 17 to 20 clones per time point. In the 3.5-year period prior to the first course of therapy, only wild-type (wt) viruses were found. As soon as 6 months after the start of zidovudine (AZT) monotherapy, all viruses contained an insertion of two aa between positions 68 and 69 of the RT and aa changes at positions 67 and 215, a combination conferring resistance to multiple nucleoside analogs. After termination of therapy, the insertion mutants were rapidly and completely replaced by the wt viruses. In turn, the insertion mutants replaced the wt viruses after initiation of therapy with 3TC, d4T, and saquinavir. After termination of triple therapy, the wt viruses completely replaced the mutants within 1 month, which is markedly faster than has been observed earlier for the replacement of AZT-resistant viruses. Fast replacements of the mutant virus populations after termination of therapy indicate gross competitive disadvantage of the insertion mutant in the absence of therapy, which we estimated by using several models. The insertion mutants attained high virus loads, demonstrating that virus load cannot be used as a direct measure of virus fitness.

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.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 remained400 copies/ml after 12 weeks of treatment. Follow-up of this study was 48 weeks.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-RNA400 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-RNA400 copies/ml at their last follow-up visit. Ten per cent of patients discontinued study medication due to adverse events.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.

Liver enzyme elevation (LEE) is commonly observed after combination antiretroviral therapy (ARVT) for HIV infection is begun. Potential risk factors for LEE after treatment with ritonavir and saquinavir with or without stavudine were investigated in 208 HIV-infected patients, by use of the Cox proportional hazard model. Eighteen patients (9%) developed LEE during the 48-week follow-up. Multivariate analysis, adjusted for baseline levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), showed that hepatitis B surface antigen (HBsAg) positivity (relative risk [RR], 8.8; 95% confidence interval [CI], 3.3-23.1) and the use of stavudine (RR, 4.9; 95% CI, 1.5-16.0) were the only significant risk factors for developing LEE. After LEE occurred, ALT and AST concentrations decreased by50% in 13 of 14 patients who continued ARVT during LEE. In this study, it appeared safe to continue ARVT during LEE; however, more data from larger studies are required to confirm this finding.

Objective: To identify genotypic drug resistance patterns of HIV-1 in patients who were extensively pretreated with anti-HIV drugs and not responding to their current antiretroviral combination therapy. Methods: Drug susceptibility of the viruses was tested by a phenotypic recombinant virus assay. Genotypic analysis of HIV resistance was performed by sequencing of the amino-terminal part of the corresponding reverse transcriptase (RT) gene (amino acids 1-280) for serum-derived and recombinant viruses. Results: Among viruses from 92 patients studied, three (3%) viruses contained a T215Y amino-acid change as well as a previously unseen combination of an aminoacid change at codon 67 (N→E/S) and a two amino-acid insertion between codons 68 and 69 of the RT gene of HIV-1. Phenotypic resistance analysis showed high levels of resistance to zidovudine, lamivudine and stavudine (in all patients) and moderate levels of resistance to didanosine and zalcitabine (in two patients), whereas neither serum-derived nor recombinant viruses contained previously known amino-acid changes conferring resistance to didanosine, zalcitabine, lamivudine and stavudine. However, all recombinant viruses contained an insertion of two amino acids between codons 68 and 69 of RT as well as an amino-acid change at codon 67, as was seen in the serum-derived viruses. Conclusions: Antiretroviral therapy including zidovudine may yield replicating viruses with a two amino-acid insertion in RT in combination with amino-acid changes at codons 67 and 215, which are highly resistant to lamivudine and stavudine on top of zidovudine and have unpredictable susceptibility to didanosine and zalcitabine despite lack of previously reported corresponding resistance-associated amino-acid changes. It is currently unknown what regimens can induce the emergence of this type of multidrug-resistant viruses. This will only be elucidated when resistance assays are capable of detecting these mutants.

Treatment of human immunodeficiency virus (HIV) infected persons with potent antiretroviral combination therapy results in a strong decline of the viral load in the blood. Whether this effect is reached in all tissues and different infected cell types is an important question. There are several potential virus reservoirs. Lymphoid tissue constitutes the largest virus compartment. With potent, often protease inhibitor containing combinations the HIV-RNA decline in lymphoid tissue runs parallel to that in the blood. The central nervous tissue is a potentially important reservoir, because of the limited penetration of several antiretrovirals, especially protease inhibitors. A few short studies with different combinations showed a decline of the amount of virus in the cerebrospinal fluid. The risk of local resistance developing is not known. There are only few studies of the effects of potent anti-HIV therapy on semen but prostate and testis tissue do not appear inaccessible to treatment. The reservoir of latently infected cells that cannot be reached by the immune system or by the viral replication inhibiting therapy, can possibly be reached with immune stimulating agents. This will cause HIV replication and cell death, while the anti-HIV therapy will prevent further replication of the produced virions. This approach is still experimental, however.

The presence of syncytium-inducing (SI) human immunodeficiency virus type 1 (HIV-1) variants is predictive for accelerated progression to AIDS. This study showed that a 4-year survival with AIDS also occurred significantly more often for patients who lacked SI variants. However, multivariate Cox analysis excluded the predictive value of SI viruses for rapid death as being independent from low CD4+ T cell counts. Incidence of appearance of SI variants was increased in persons with CD4+ T cell counts + T cell counts

First clinical virological evaluation of anti-HIV treatment with HIV reverse transcriptase (RT) and protease inhibitors.Descriptive.Academic Medical Centre of the University of Amsterdam, the Netherlands.From January 1, 1996, until May 1, 1997, HIV-RNA levels were determined in sequential serum or plasma samples obtained sequentially of 384 patients over a period of 3.1 years on average (minimum 0.5, maximum 10 years). Of these patients 318 had sustained treatment for at least 6 months. The effect on HIV-RNA serum or plasma levels was evaluated in this particular group, of which 224 (70.4%) had been pretreated with antiretroviral drugs (experienced patients) and 94 (29.6%) had not (naive patients).Of the naive patients 8.5% were treated with a combination of two, 89.4% with three and 2.1% with four anti-HIV drugs. Preceding their current treatment, an average of more than two other anti-HIV regimens had been administered to the experienced patients. From 1987 until May 1997 a total of 834 treatments were registered among the 224 patients: 202 mono, 223 double, 340 triple, 60 quadruple and 9 other combination treatments. After six months 84% of the triple combination treatments in the naive patients and 61% in the experienced patients resulted in RNA levelsor = 10(3) copies/ml (p = 0.008). Of 68 patients who failed on treatment 36 (52.9%) showed resistance associated mutations in HIV reverse transcriptase. In 6/43 (14%) of these patients resistance associated mutations in protease were found as well. Genotypic resistance could not always be confirmed phenotypically.Our preliminary results indicate that in a majority of cases triple combination treatment including at least one HIV protease inhibitor was successful. Nevertheless, in 16% of the therapy-naive and 39% of the therapy-experienced patients the anti-HIV effect of treatment was insufficient.

Triple combination treatment of HIV-1 infection using two reverse transcriptase inhibitors and a protease inhibitor can result in significant and sustained decreases in the quantity of viral RNA in peripheral blood. Lymphoid tissue, however, constitutes the major reservoir of HIV in infected patients. Study of the viral burden in these tissues has provided additional insight in the efficacy of antiretroviral treatment.Patients were randomized into two groups in order to study differences in the development of resistance to reverse transcriptase inhibitors. Group I started treatment with all three drugs simultaneously. Group II started with ritonavir monotherapy, aiming at initial reduction in virus production before the addition of lamivudine and zidovudine 3 weeks later.Changes in the amount of HIV in plasma and tonsillar lymphoid tissue during 24 weeks of treatment with ritonavir, lamivudine and zidovudine were studied by reverse transcriptase polymerase chain reaction.Thirty-three antiretroviral-naive HIV-infected patients were included for analysis. After 24 weeks, median CD4+ cell count increased by 152 x 10(6)/l and median plasma viral RNA levels decreased by at least 2.87 log10 copies/ml. In 88% of the patients remaining on treatment, plasma RNA levels were below the quantification limit of the assay used (mean, 2.4 log10 copies/ml). The lymphoid tissue viral burden, ranging from 9.16 to 8.52 log10 copies/g at baseline, was markedly reduced with at least 2.1 log10 copies/g by week 24 in the five patients analysed. Eight patients (24%) withdrew because of side-effects. In one patient in group II, ritonavir and lamivudine resistance-associated mutations developed.Treatment with this triple antiretroviral drug combination produced a durable and strong decrease of HIV-1 RNA burden in both plasma and lymphoid tissue.

The effect of antiretroviral therapy on both T-cell numbers and T- cell function in peripheral blood was studied. CD4+ and CD8+ T-cell numbers, T-cell reactivity to CD3 monoclonal antibodies (mAb), and viral RNA load date were obtained from patients treated for at least 28 weeks with either the HIV-1 protease inhibitor ritonavir, the nonnucleoside HIV- 1 reverse transcriptase (RT) inhibitor nevirapine, or the nucleoside- analogue RT inhibitor zidovudine. Compared with both RT inhibitors, treatment with the protease inhibitor ritonavir resulted in the most significant and persistent elevation of CD4+ and CD8+ T-cell counts. However, in vitro T-cell functional improvement was of limited duration in the ritonavir-treated group and was inversely correlated with viral RNA load changes during the entire follow-up period. Thus, despite what can be assumed of responses during RT inhibitor therapy, quantitative responses on therapy did not necessarily correlate with qualitative immunologic responses, as can be seen during treatment with ritonavir. For optimal immune reconstitution, both numeric and functional immunologic improvements are essential. During antiretroviral therapy, measurement of in vitro improvement in immune function will be useful as a correlate for transient drug-induced alteration of immunodeficiency.

The objective of this study was to determine the efficacy and safety of adding zidovudine to continuous treatment with lamivudine in symptomatic human immunodeficiency virus type 1 (HIV-1)-infected patients. Forty patients were monitored throughout lamivudine monotherapy and subsequent combination therapy with lamivudine and zidovudine, which was initiated because of disease progression, declining CD4 cell counts or prolonged use of lamivudine. Eleven of these patients had been treated with zidovudine before the start of the study. The median CD4 cell count at the start of lamivudine monotherapy was 200 x 10(6) cells/l. After a median interval of 69 weeks (range 23-102 weeks), the median CD4 cell count had dropped to 110 x 10(6) cells/l. Initial improvements in all laboratory markers for antiretroviral efficacy were observed after the addition of zidovudine. The median CD4 cell count remained 18% above baseline after 48 weeks of treatment with lamivudine and zidovudine, however plasma HTV-1 RNA load and CD4 cell counts returned towards baseline during prolonged treatment in most patients. The combination was well tolerated, although anaemia was observed in nine patients. Repeated measures analysis of variance suggested a superior effect of lamivudine monotherapy in patients who had previously used zidovudine. In conclusion, zidovudine was found to be effective in patients who have been treated with lamivudine. The study stresses the need to further define the mechanisms underlying this prolonged antiviral effect.

By studying changes in the clonal composition of HIV-1 populations during the first weeks of zidovudine (ZDV) treatment before the development of ZDV resistance-conferring mutations, we demonstrated previously a selective inhibition of nonsyncytium-inducing (NSI) HIV-1, even when present as coexisting population in individuals also harboring syncytium-inducing (SI) HIV-1. In this study, we observed the opposite in individuals receiving didanosine (ddI) treatment. In these individuals (n = 7) a median -0.98 log change (range -1.55-0.08) in infectious cellular SI load was observed, whereas the coexisting NSI load was only minimally affected (median -0.15 log, range -1.27-0.50; P = 0.03). The virus phenotype-dependent treatment responses were independent of the clonal composition of HIV-1 populations at baseline. Individuals treated with a combination of ZDV and ddI revealed an equal decline of both NSI and SI infectious cellular load (n = 4; NSI: median -1.55 log, range -2.19 to -1.45; SI: median -1.47 log, range -1.81 to -0.86; P = 0.56). To test the hypothesis that the previously reported optimal activation of ZDV and ddI in activated and resting T cells, respectively, in combination with the differential T cell tropism of NSI and SI HIV-1 is the basis for the observed virus phenotype specific efficacy of nucleoside analogs, we studied the effect of treatment with a protease inhibitor that does not require intracellular activation. Individuals receiving ritonavir (n = 4) indeed showed equal declines in NSI and SI infectious cellular load (NSI: median -2.37 log, range -2.59 to -2.16; SI: median -2.82 log, range - 3.14 to -2.50; P = 0.25). Our data suggest HIV-1 phenotype as an additional parameter in the design of optimal treatment regimens.

To compare the safety and efficacy or oral ganciclovir with intravenous ganciclovir for the maintenance therapy of cytomegalovirus (CMV) retinitis in AIDS patients.Multicenter, randomized, open-label study, with both masked and unmasked ophthalmic assessments.Patients with AIDS and stable CMV retinitis were randomized after an induction course of intravenous ganciclovir (5 mg/kg twice daily) to receive maintenance therapy with oral ganciclovir (500 mg six times daily) or intravenous ganciclovir (5 mg/kg once daily).The primary endpoint of the study was time to progression of CMV retinitis from the start of maintenance therapy.The mean time to progression, evaluated by funduscopy was 109 days for the intravenous group, and 86 days for the oral group (P = 0.02). The masked photographic assessment revealed shorter time to progression for both oral and intravenous groups, as compared with funduscopy data, and showed no significant difference between the two treatment groups: 62 days for intravenous ganciclovir and 51 days for oral ganciclovir (P = 0.15). Diarrhea and neutropenia were the most frequent reported events in both groups, with the incidence of sepsis more than double in the intravenous compared with the oral ganciclovir group (3 versus 8.5%).Oral ganciclovir offers a reasonable alternative to intravenous ganciclovir for the maintenance therapy of CMV retinitis in AIDS patients.

To evaluate the measurement of intraocular antibody production and detection of DNA by the polymerase chain reaction (PCR) for diagnosis of the causative microorganism in patients with AIDS and necrotizing retinitis.Paired serum and aqueous humour samples obtained from 28 patients with AIDS and necrotizing retinitis, seen between January 1987 and March 1992, were analysed for intraocular antibody production against cytomegalovirus (CMV), varicella zoster virus, herpes simplex virus, Epstein-Barr virus, and Toxoplasma gondii. Specific antibody titres in the inflamed eye and in the circulation were related to total immunoglobulin G content in the aqueous humour and serum. In addition, PCR analysis was performed in 15 samples. Results were compared to the final diagnosis, which was based on the subsequent clinical course. Results were also related to parameters describing the immune state of the patients: CD4 count, time between diagnosis of an AIDS-defining illness and retinitis, and time of survival following the diagnosis of retinitis.In 11 (39%) out of 28 patients we found local intraocular antibody production which correlated with the final diagnosis (one out of two cases with acute retinal necrosis, three out of five cases with toxoplasma retinitis, and eight out of 21 patients with CMV retinitis). In all 13 patients with CMV retinitis PCR analysis detected CMV DNA. In one patient with the clinical diagnosis of Toxoplasma retinitis, Toxoplasma DNA could be determined, whereas in the same sample CMV DNA was also found. In yet another patient with Toxoplasma retinitis only CMV DNA could be detected. A relationship between results of local antibody determination with either CD4 counts, or the time interval between AIDS-defining illness and retinitis, or survival time after diagnosis of retinitis could not be established. CD4 counts were higher than 50 x 10(6)/l in eight out of 19 patients with CMV retinitis. No complications of paracentesis were seen.Detection of intraocular antibody production and PCR analysis are quick and safe procedures and helpful tools for diagnosis of the involved pathogen in AIDS patients with a necrotizing retinitis. Negative results of local antibody production, even in the presence of detectable viral DNA, could not be related to the parameters of a more deteriorated immune status of these patients.

To compare the safety and efficacy of 2 doses of lamivudine given in combination with zidovudine with continued zidovudine monotherapy.Double-blind, randomized, multicenter, comparative trial of 223 patients treated for 24 weeks.Patients from 32 hospitals in Europe were enrolled throughout a 1-year period.Adult human immunodeficiency virus type 1 (HIV-1)-positive, zidovudine-experienced (or = 24 weeks prior zidovudine) patients with CD4+ cell counts between 0.10 and 0.40 x 10(9)/L (100-400 cells/microL).Patients received either 200 mg of zidovudine every 8 hours, 150 mg of lamivudine every 12 hours plus zidovudine, or 300 mg of lamivudine every 12 hours plus zidovudine for 24 weeks. All patients were then allowed to receive zidovudine and open-label lamivudine combination therapy. Twelve patients withdrew because of adverse events during the 24-week treatment period.Efficacy was measured by evaluating immunological and viral load changes, and safety was assessed by evaluating clinical manifestations and laboratory indexes of toxic effects.Patients receiving low- or high-dose combination therapy had greater treatment effects compared with patients receiving continued zidovudine monotherapy during the first 24 weeks as documented by changes in CD4+ cell counts (+0.04 vs +0.03 vs -0.02 x 10(9)/L, respectively; P.001); log10 HIV-1 RNA as measured by the Roche assay (-0.96 vs -0.77 vs +0.07 copies/mL, respectively; P.001) or log10 HIV-1 RNA measured by the quantitative nucleic acid sequence-based amplification assay (-0.59 vs -1.06 vs -0.02 copies/mL, respectively; P.011); and immune-complex dissociated (ICD) p24 antigen (-74% vs -68% vs +27%, respectively; P.001). There were no statistically significant differences in viral measurements, in CD4+ cell counts, or in safety profile between the groups receiving 2 doses of lamivudine in combination with zidovudine. The effects on CD4+ cell counts and ICD p24 antigen were sustained throughout 48 weeks for patients continuing combination therapy. Patients switching to combination therapy at week 24 showed improvement.In zidovudine-experienced HIV-1-infected patients, combination treatment with lamivudine and zidovudine is well tolerated and provides greater and more sustained increases in CD4+ cell counts and decreases in viral load than continued zidovudine monotherapy.

Reverse-transcriptase inhibitors have only moderate clinical efficacy against the human immunodeficiency virus type 1 (HIV-1). Ritonavir is an inhibitor of HIV-1 protease with potent in vitro anti-HIV properties and good oral bioavailability.We evaluated the antiviral activity and safety of ritonavir in a double-blind, randomized, placebo-controlled phase 1 and 2 study of 84 HIV-positive patients with 50 or more CD4+ lymphocytes per cubic millimeter. The patients were randomly assigned to one of four regimens of ritonavir therapy, or to placebo for four weeks and then (by random assignment) to one of the ritonavir regimens.During the first 4 weeks, increases in CD4+ lymphocyte counts and reductions in the log number of copies of HIV-1 RNA per milliliter of plasma were similar among the four dosage groups, but in the three lower-dosage groups there was a return to base-line levels by 16 weeks. After 32 weeks, in the seven patients in the highest-dosage group (600 mg of ritonavir every 12 hours), the median increase from base line in the CD4+ lymphocyte count was 230 cells per cubic millimeter, and the mean decrease in the plasma concentration of HIV-1 RNA (as measured by a branched-DNA assay) was 0.81 log (95 percent confidence interval, 0.40 to 1.22). In a subgroup of 17 patients in the two higher-dosage groups, RNA was also measured with an assay based on the polymerase chain reaction, and after eight weeks of treatment there was a mean maximal decrease in viral RNA of 1.94 log (95 percent confidence interval, 1.37 to 2.51). Adverse events included nausea, circumoral paresthesia, elevated hepatic aminotransferase levels, and elevated triglyceride levels. Ten withdrawals from the study were judged to be related to ritonavir treatment.In this short-term study, ritonavir was well tolerated and had potent activity against HIV-1, but its clinical benefits remain to be established.

To review the estimated incidence of cytomegalovirus (CMV) disease, its diagnosis and currently accepted treatments and those under investigation. CMV DISEASE IN PATIENTS WITH HIV INFECTION: The most frequently occurring manifestation of CMV disease is retinitis, occurring in approximately 20-40% of patients. Oesophagitis and generalized infection are also common.At present, diagnosis relies on specific histopathology as serology is unreliable and CMV culture lacks sensitivity and specificity. Assessment of the presence of CMV-specific proteins and polymerase chain reaction assays of CMV DNA may prove useful.Intravenous ganciclovir and foscarnet are equally effective for the treatment of CMV disease, but ganciclovir is generally regarded as the primary treatment option due to its relative ease of administration. Combination therapy with these agents is also effective in the treatment of CMV retinitis. As well as patients with sight-threatening retinitis, patients with peripheral retinitis benefit from immediate treatment. Local treatment with a ganciclovir implant or intravitreal injection is effective, but does not provide protection against ocular complications, infection of the contralateral eye and extraocular disease. Oral ganciclovir is virtually as effective as intravenous administration for secondary prophylaxis versus maintenance treatment for CMV retinitis with the advantage of a more favourable adverse-effect profile.Intravenous ganciclovir and foscarnet are equally effective in the treatment of CMV disease. Oral ganciclovir is effective in secondary prophylaxis and provides a welcome alternative to intravenous maintenance treatment.

To determine whether a mucosal cytokine-mediated inflammatory response is involved in cryptosporidial or microsporidial diarrhoea, as well as in diarrhoea of unknown origin in HIV-infected patients.Prospective study.Jejunal biopsies were obtained from HIV-infected patients with diarrhoea. Controls were HIV-infected and HIV-seronegative patients without diarrhoea. Two biopsies were homogenized immediately and two other biopsies were first cultured for 20 h. Cytokines [tumour necrosis factor (TNF), interleukin (IL)-1 beta, IL-6, IL-8, IL-10], soluble TNF receptors (sTNFR) p55 and p75, and soluble IL-2 receptor (sIL-2R) were assessed in the homogenates and in the supernatants by sandwich enzyme-linked immunosorbent or enzyme-linked binding assays. The cytokine receptors were also measured in serum.Six HIV-infected patients with cryptosporidiosis, six with microsporidiosis, seven with diarrhoea of unknown origin, seven without diarrhoea, and seven HIV-seronegative patients were eligible. Four patients were excluded because of the presence of other pathogens. No cytokines were detected in immediately homogenized jejunal tissue. Following culture, IL-6 and IL-8 levels were higher in HIV-infected patients with diarrhoea of unknown origin than in HIV-seronegative controls without diarrhoea, although this was not statistically significant. No differences in serum or post-culture supernatant sTNFR p55 and p75 levels existed between the HIV-infected patients with or without diarrhoea. sTNFR, IL-1 beta, IL-10 and the sIL-2R were only detected in low amounts or not at all, and were equally distributed among all patient groups.This study indicates that mucosal cytokine-mediated inflammatory responses do not play an important role in the pathogenesis of different types of diarrhoea in HIV-infected patients. These results do not support the use of immunomodulatory therapy in these patients.