Antiretroviral therapy for HIV infection in 1996. Recommendations of an international panel. International AIDS Society-USA

We report on a retrospective study evaluating infectious morbidity associated with totally implantable venous access devices (TIVAD) (Port-A-Cath) in HIV-infected patients. This study of 84 consecutive HIV-infected patients requiring 89 TIVAD between January 1990 and October 1993 was performed in the Department of Infectious Diseases H?pital de l'Institut Pasteur, Paris, France. The total number of catheter days was 11,595. Eighteen of 89 patients with TIVAD (20%) were infected, causing 25 infectious events (25/89: 28%) among 17 different patients (17/84: 20%). The infection rate was 0.22 per 100 catheter days. Mean onset of infection was 82 days. Twenty microorganisms were isolated: Staphylococcus aureus in eight cases (40%), coagulase-negative Staphylococcus in six cases (30%), Streptococcus D faecalis in one case; Gram-negative bacilli were found in five cases (25%). All patients received an intravenous antibiotherapy combined with a local lock treatment in eight cases. Nine TIVAD removals were performed. One death was related to the TIVAD infection. No additional predisposing factor for infection was identified other than the implied condition of the HIV infection. The population and material in this study were homogeneous. The TIVAD infection rate was comparable to other published reports. Prospective evaluation comparing tunneled catheter and TIVAD in HIV-infected patients is needed.     

Increasing survival in AIDS patients with cytomegalovirus retinitis treated with combination antiretroviral therapy including HIV protease inhibitors

Intravascular Doppler is widely used for experimental studies in the coronary circulation. We designed this study to assess baseline bloodflow and arteriolar resistance in the porcine renal circulation and to study the vasomotor responses of vasoactive drugs. In anesthesized piglets (n = 15), renal arterial diameter was measured with quantitative angiography and blood flow velocity with a Doppler wire (Cardiometrics). Bloodflow and resistances were calculated at baseline and after injection of vasoactive drugs (isosorbide dinitrate, papaverine). This allowed us to determine the renal bloodflow reserve (the capacity of the kidney to augment basal bloodflow). Injection of isosorbide dinitrate was associated with an increase in average peak velocity of 64% (P < 0.01) and a small (from 4.5 to 4.74, P < 0.01) but significant increase in renal artery diameter, resulting in an increase in bloodflow of 82% (P < 0.01) and a decrease in arteriolar resistance of 46% (P < 0.01). Bloodflow returned to baseline (4.76 +/- 1.48 mL/s) approximately 5 min after isosorbide injection. Average Peak Velocity increased almost twofold after papaverine injection (60 +/- 10 to 108 +/- 24 cm/sec, P < 0.01). There was a significant (P < 0.01) increase in arterial bloodflow of 96% in the right and 79% in the left renal artery after injection of papaverine with a corresponding significant (P < 0.01) decrease in arteriolar resistance of 49% in the right and 44% in the left renal artery. Using a combination of quantitative angiography and intravascular Doppler allows easy measurement of baseline renal blood flow and of the effects of vasodilator drugs on bloodflow and resistance. The results show that a vasodilatator reserve exists in the renal circulation but is less marked than that reported in the coronary circulation.     

Effectiveness of potent antiretroviral therapy on time to AIDS and death in men with known HIV infection duration. Multicenter AIDS Cohort Study Investigators

CONTEXT: Time to development of acquired immunodeficiency syndrome (AIDS) and time to death have been extended with the increased use of combination therapy and protease inhibitors. Cohort studies following up persons with human immunodeficiency virus (HIV) infection in periods characterized by different therapies offer the opportunity to estimate therapy effectiveness at the population level. OBJECTIVE: To assess the effectiveness of self-reported, long-term potent antiretroviral therapy in a cohort of 536 men whose duration of HIV infection was known (seroconverters). DESIGN: Cohort study. The cohort was compared for time to development of AIDS and time to death in 1984 to 1990, 1990 to 1993, 1993 to July 1995, and July 1995 to July 1997 when the major treatments were no therapy, monotherapy, combined therapy, and potent antiretroviral therapy, respectively. Survival analysis methods with time zero set as the date of seroconversion and incorporating staggered entries into each period were used. Mean CD4 cell change, stratified by infection duration, was determined for each period using a random effects model. SETTING: The Multicenter AIDS Cohort Study (MACS) in 4 urban areas (Baltimore, Md; Chicago, III; Los Angeles, Calif; and Pittsburgh, Pa). PARTICIPANTS: A total of 5622 men who were 18 years or older were enrolled into MACS. Of the 5622, there were 2191 HIV-positive individuals at enrollment. Of the 3431 men who were HIV-negative, 536 were observed to seroconvert and were followed up for up to 13 years. The group of 536 who seroconverted constituted the study population. MAIN OUTCOME MEASURES: Time from seroconversion to development of AIDS and to death and change in CD4 cell count. RESULTS: A total of 231 seroconverters developed AIDS, and 200 men died. Using 1990 to 1993 as the reference period, the relative hazard of AIDS was 1.04 (95% confidence interval [CI], 0.73-1.48) during 1993 to July 1995 and 0.35 (95% CI, 0.20-0.61) during July 1995 to July 1997. Relative hazards of death were 0.87 (95% CI, 0.58-1.31) and 0.62 (95% CI, 0.38-1.01 ) for the same periods. The relative time (the factor by which times are contracted or expanded) to development of AIDS was 0.97 (95% CI, 0.86-1.09) for 1993 to July 1995 and 1.63 (95% CI, 1.40-1.89) for July 1995 to July 1997. Relative survival time for 1993 to July 1995 was 1.01 (95% CI, 0.91-1.12) and for July 1995 to July 1997 was 1.21 (95% CI, 1.07-1.36) relative to 1990 to 1993. The rate of CD4 cell count decline in July 1995 to July 1997 was significantly lower (P<.05) compared with the previous 2 periods. CONCLUSIONS: In the calendar period when potent antiretroviral therapy was introduced, the time to development of AIDS and time to death were extended, and rate of CD4 cell count decline was arrested.     

Improvement of chronic diarrhoea in patients with advanced HIV-1 infection during potent antiretroviral therapy

The functional projection of the medial perforant path (MPP) to different CA3 subfields was studied in urethan-anesthetized rats using current source density analysis. MPP stimulation resulted in an early-latency (presumed monosynaptic) sink with onset of 2-3 ms at the distal apical dendritic layer of CA3 (stratum lacunosum molecule) and a long-latency (presumed disynaptic, >7 ms) sink at stratum lucidum and radiatum of CA3. The population spike (onset 5. 3-6.1 ms), a sink at CA3 pyramidal cell layer, was observed 67% of the time (12 of 18 rats) in CA3a, 44% (8 of 18) in CA3b and 58% (7 of 12 rats) in CA3c following MPP stimulation. Population spike was not observed during presumed disynaptic excitation of CA3. Both early-latency sink (excitatory postsynaptic potential) and population spike in CA3 revealed robust paired-pulse facilitation (PPF). In contrast, little PPF was found for the MPP-evoked excitatory sink at the middle molecular layer of the dentate gyrus. The data suggested that the entorhinal cortex provides a strong monosynaptic excitation of different subfields of CA3. A direct entorhinal to CA3 input bypasses the dentate gyrus and may play a role in normal hippocampal signal processing and neural plasticity.     

Gene therapy for infectious diseases: the AIDS model

Genetic manipulation of somatic cells may be of therapeutic value in a variety of infectious diseases, particularly in human immunodeficiency virus (HIV) infection. Stable insertion of custom-designed 'resistance genes' into cells susceptible to HIV could reduce the viral burden in infected individuals and potentially retard the characteristic progressive immune dysfunction. Alternatively, ectopic expression of genes that encode viral antigens might induce potent antiviral immune responses and form the basis for novel prophylactic and therapeutic vaccines. While laboratory studies have proved that the approach works in principle, preclinical and clinical studies will be necessary to evaluate the therapeutic benefit of such gene-based therapies.     

Lack of reactivation of cytomegalovirus (CMV) retinitis after stopping CMV maintenance therapy in AIDS patients with sustained elevations in CD4 T cells in response to highly active antiretroviral therapy

The suppression of human immunodeficiency virus (HIV) replication and elevation in CD4 cells observed with protease inhibitor combination regimens known as HAART (highly active antiretroviral therapy) may allow AIDS patients to undergo an immune recovery that allows them to suppress the progression of cytomegalovirus (CMV) retinitis. Eleven AIDS patients receiving HAART with healed CMV retinitis in whom CMV-specific maintenance therapy was discontinued were studied. Median CD4 cell counts were 42 before the initiation of HAART and 183 at discontinuation of anti-CMV therapy. While a median 1.1 log10 drop in plasma HIV-1 RNA was obtained between starting HAART and withdrawal of maintenance therapy for CMV, only 3 of 11 patients maintained plasma HIV RNA below the limits of detection. Reactivation of CMV retinitis after withdrawal of anti-CMV therapy did not occur in any of the patients observed for a median of 156 days (range, 92-558).     

The impact of antiretroviral therapy on AIDS survival observed in a province-wide drug treatment programme

Erythrocytosis is a relatively common complication of renal transplantation. Recent observations indicate that angiotensin-converting enzyme inhibitors correct renal transplant erythrocytosis. Other drugs to inhibit the renin-angiotensin system have been developed recently. The newest of these is losartan, a specific antagonist of the angiotensin II type I receptor. We report three patients in which the use of losartan controlled posttransplant erythrocytosis. Our findings suggest that losartan can be effective and safe in the treatment of posttransplant erythrocytosis.     

Hepatobiliary diseases in patients with AIDS: focus on AIDS cholangiopathy and gallbladder disease

Since there have been very few studies on nucleolar signaling, an attempt was made to establish nucleolar signal pathways which link the cell membrane to the nucleolus for the transfer of extracellular signals. Two pathways were studied. One was the G alpha s mediated cAMP pathway where two signal molecules were yielded, including RII and protein kinase A. The other was the G alpha q mediated DAG/IP3 pathway which yields two signals including protein kinase C and IP3/Ca2+. By the studying isolated nucleoli from resting liver, regenerating liver or weak carcinogen thioacetamide treated liver, it was possible to detect protein kinase A (PKA), protein kinase C (PKC) and RII subunits. In addition, CK2 was detected. It was found that external signals transmitted through G protein coupled receptors could reach into the nucleolus and that physical translocation of signal molecules was an integral step involved in membrane-nucleolus linked pathways. When an in vitro assay of the above signal molecules was carried out using [gamma-32P]-ATP, most kinase dependent phosphorylation was via the major CK2 (more than 95%). Therefore, it is suggested that the major CK2 dependent pathway is involved in 'house keeping' for nucleolar integrity and the minor pathways, dependent on PKA, PKC and others, are involved in subtle regulatory mechanisms such as 'extra-house-keeping' activities by nucleolar chromosomal remodeling.     

Medical issues associated with international competition. Guidelines for the traveling physician

This article describes the concerns and duties of the team physician while traveling for international competition. The medical preparedness and social interaction required of the team physician are addressed.     

Incidence of immune recovery vitritis in cytomegalovirus retinitis patients following institution of successful highly active antiretroviral therapy

This study was conducted to determine the likelihood of the development of a new ocular inflammatory syndrome (immune recovery vitritis, IRV), which causes vision loss in AIDS patients with cytomegalovirus (CMV) retinitis, who respond to highly active antiretroviral therapy (HAART). We followed 30 HAART-responders with CD4 cell counts of >/=60 cells/mm3. Patients were diagnosed with IRV if they developed symptomatic vitritis of >/=1+ severity associated with inactive CMV retinitis. Symptomatic IRV developed in 19 (63%) of 30 patients and in 26 (59%) of 44 eyes over a median follow-up from HAART response of 13.5 months. The annual incidence of IRV was 83/100 person-years. Excluding patients with previous cidofovir therapy did not significantly alter the time course of IRV (P=.79). These data suggest that IRV develops in a significant number of HAART-responders with CMV retinitis and is unrelated to previous cidofovir therapy.     

New issues in the management of cytomegalovirus retinitis in AIDS patients

The pharmacokinetic profile of ibuprofen (CAS 15687-27-1) in a Fast Melting Tablet (FMT), a modified release formulation (encapsulation of the active ingredient in gastroresistant microcapsules), was compared with that of sugar coated tablets (SCT; Moment 200). In the following paper an open, single dose, cross-over study in eighteen healthy volunteers (9 males and 9 females--mean age 27 years) is reported. The results of the study demonstrated that the rate of absorption of the FMT was markedly slower than that of the SCT. In fact, the geometric mean peak plasma concentration (Cmax) and median peak time (tmax) were 12.04 micrograms/ml at 3.5 h with the new formulation, and 18.71 micrograms/ml at 1 h with the SCT, respectively. The longer absorption time and diminished peak plasma concentration did not affect the extent of absorption of the two formulations, expressed by AUCo-t and AUC (90% confidence interval: 0.89-1.00 for AUCo-t and 0.92-1.03 for AUC). The safety profile of both drugs proved to be very good and no clinically significant adverse events were observed.     

Do dual nucleoside regimens have a role in an era of plasma viral load-driven antiretroviral therapy?

This study was undertaken to characterize predictors of response to double nucleoside combinations among 245 human immunodeficiency virus-infected persons initiating antiretroviral therapy. The median time for receiving antiretroviral therapy in this group was 6 months, and the plasma virus load was 58,000 copies/mL. The most commonly prescribed regimens were zidovudine/lamivudine (154 subjects, 63%) and stavudine/lamivudine (46 subjects, 19%). A total of 96 (39%) subjects had their virus load decrease to < 500 copies/mL after the initiation of therapy. Of the 245 study subjects, 102 (41.6%) had > or = 5 months of follow-up and two or more consecutive virus load determinations performed after the start of antiretroviral therapy. Multivariate analysis demonstrated that baseline virus load was the only significant factor associated with obtaining two or more plasma virus loads of < 500 copies/mL. Overall, these data demonstrate that dual nucleoside therapy (using currently licensed agents) cannot reliably achieve a high level of suppression of plasma virus load.     

Cytarabine therapy for progressive multifocal leukoencephalopathy in patients with AIDS

To evaluate the efficacy and safety of intravenous cytarabine in the treatment of AIDS-associated progressive multifocal leukoencephalopathy (PML), we reviewed the charts of all human immunodeficiency virus-infected patients with PML who were seen during a 28-month period at our institution. Patients with biopsy-proven PML were offered therapy with intravenous cytarabine (2 mg/[kg.d] for 5 days every 4 weeks). The diagnosis of PML was histologically confirmed for 13 patients. The median CD4 cell count was 91 x 10(6)/L. A median of three courses of cytarabine was administered to eight patients. Two patients developed mild drug-related toxicities. Clinical and/or radiological signs of improvement were observed for three patients treated with cytarabine; no signs of improvement were noted for the untreated patients. Median survival time after the diagnosis of PML was 102 days (range, 46-220 days) for patients who received cytarabine and 60 days (range, 28-72 days) for untreated patients matched for Karnofsky scores (P = .06, logrank test). Although cytarabine is well tolerated by patients with AIDS and PML, only modest short-term clinical improvement in the conditions of patients treated with the drug has been observed, with no significant impact on survival.     

Rapid diagnosis of cytomegalovirus encephalitis in patients with AIDS using in situ hybridisation

AIMS: To evaluate the presence of cytomegalovirus (CMV) DNA in the cerebrospinal fluid of patients with AIDS and suspected viral encephalitis using an in situ hybridisation assay with digoxigenin labelled CMV DNA probes. METHODS: The presence of CMV DNA was evaluated in cerebrospinal fluid cells of 10 patients with AIDS using in situ hybridisation. The positivity of CMV DNA was confirmed by the presence of CMV induced antigens in the same specimens. The presence of CMV DNA and CMV induced antigens was also analysed in peripheral blood leucocytes. The time required to perform the in situ hybridisation assay was about eight hours. RESULTS: The in situ hybridisation assay was sensitive, specific, and provided good resolution. Six patients proved positive for the presence of CMV DNA in CSF cells and all six also proved positive for CMV DNA in blood leucocytes. Of the six CMV positive patients, five were treated with specific antiviral drugs: of these, one died during the treatment while four clinically recovered after one month of treatment. CONCLUSIONS: The in situ hybridisation assay using digoxigenin labelled CMV DNA probes can be used as a valuable diagnostic test for the detection of CMV DNA in the cerebrospinal fluid cells of patients with suspected CMV encephalitis and can therefore prompt adequate antiviral therapeutic intervention.