Cytomegalovirus infection in HIV-infected patients in the era of combination antiretroviral therapy.

BACKGROUND: Cytomegalovirus infection dramatically decreased with the introduction of antiretroviral therapy. Whether incidence, clinical characteristics and prognosis of cytomegalovirus in HIV infected patients, has changed over time is. scarcely known. METHODS: Retrospective single-center study. Patients included in this study were all HIV infected patients that went to our center for any disease, and were diagnosed with cytomegalovirus, during the period 2004-2015. epidemiological, clinical and laboratory patients variables were collected in a clinical database. Clinical characteristics, incidence of cytomegalovirus and predictors of mortality during the study were assessed. Results were considered statistically significant when p < 0.05. All statistical analyses were calculated by SPSS version 20.0 (Chicago, IL,USA). RESULTS: Fifty-six cases of cytomegalovirus infection, in HIV infected patients were identified during the study period (incidence rate-1.7 cases per 1000 persons/year). The most frequent presentation was systemic illness in 43% of cases. Of note,no patients presented with ophthalmic manifestations. The 30-days mortality was 18%. Predictors of mortality were, in the univariate analysis, admission to the intensive care unit OR 32.4 (3.65-287.06) p = 0.0001, and mechanic ventilation 84 OR (8.27-853.12) p = 0.0001, and ART OR 4.1 (0.97-17.31) p = 0.044. These variables were assessed by multivariate analysis, and only mechanical ventilation was statistically significant (p < 0.05) CONCLUSION: Incidence of cytomegalovirus infection was higher than described in the antiretroviral therapy era. Clinical presentation has changed. Mechanic ventilation predicted mortality.

Subclinical cardiovascular disease in patients starting contemporary protease inhibitors.

OBJECTIVES: The aim of the study was to assess changes in and factors associated with anatomical [carotid artery intima-media thickness (CIMT)] and functional (arterial stiffness) markers of subclinical cardiovascular disease progression in antiretroviral-naïve patients starting triple combination antiretroviral therapy containing contemporary protease inhibitors. METHODS: This was a planned substudy of the ATADAR (Metabolic Effects of Atazanavir/Ritonavir Versus Darunavir/Ritonavir in Combination With Tenofovir/Emtricitabine in naïve HIV-1 Infected Patients) clinical trial (ClinicalTrials.gov identifier NCT01274780). ATADAR is a multicentre, randomized, open-label clinical trial comparing the effects of ritonavir-boosted atazanavir and darunavir, both with tenofovir/emtricitabine, in antiretroviral-naïve HIV-infected patients. Common CIMT and aortic augmentation index (AIx@75) were measured at baseline and after 12 months of follow-up. Antiretroviral treatment, traditional cardiovascular risk factors and HIV-related factors were assessed as potential predictors of CIMT and Aix@75 changes using linear regression analysis. RESULTS: Thirty-three patients were included in this pilot study. While CIMT significantly increased in the pooled population [median (interquartile range (IQR)) 68 (-13, 128) µm; P = 0.0511], AIx@75 did not [median (IQR) 1 (-6, 5)%; P = 0.8964]. Patients on darunavir showed a trend to faster CIMT progression than those on atazanavir [median change (IQR) 117 (-2, 143) vs. -6 (-58, 89) µm, respectively; P = 0.0917]. However, after adjustment in the multivariate analysis, a higher baseline Framingham score was the only factor associated with CIMT progression (coefficient 16.02; 95% confidence interval -1.04, 33.08; P = 0.064). AIx@75 change was not associated with any baseline factor. CONCLUSIONS: CIMT was a more sensitive marker of subclinical vascular disease progression than arterial stiffness in antiretroviral-naïve patients starting antiretroviral therapy with contemporary protease inhibitors. Classical risk factors but not antiretroviral therapy were associated with faster CIMT progression.

Full blood count values as a predictor of poor outcome of pneumonia among HIV-infected patients.

BACKGROUND: To evaluate the predictive value of analytical markers of full blood count that can be assessed in the emergency department for HIV infected patients, with community-acquired pneumonia (CAP). METHODS: Prospective 3-year study including all HIV-infected patients that went to our emergency department with respiratory clinical infection, more than 24-h earlier they were diagnosed with CAP and required admission. We assessed the different values of the first blood count performed on the patient as follows; total white blood cells (WBC), neutrophils, lymphocytes (LYM), basophils, eosinophils (EOS), red blood cells (RBC), hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin concentration, mean corpuscular hemoglobin, red blood cell distribution width (RDW), platelets (PLT), mean platelet volume, and platelet distribution width (PDW). The primary outcome measure was 30-day mortality and the secondary, admission to an intensive care unit (ICU). The predictive power of the variables was determined by statistical calculation. RESULTS: One hundred sixty HIV-infected patients with pneumonia were identified. The mean age was 42 (11) years, 99 (62%) were male, 79 (49%) had ART. The main route of HIV transmission was through parenteral administration of drugs. Streptococcus pneumonia was the most frequently identified etiologic agent of CAP The univariate analysis showed that the values of PLT (p < 0.009), EOS (p < 0.033), RDW (p < 0.033) and PDW (p < 0.09) were predictor of mortality, but after the logistic regression analysis, no variable was shown as an independent predictor of mortality. On the other hand, higher RDW (OR = 1.2, 95% CI 1.1-1.4, p = 0.013) and a lower number of LYM (OR 2.2, 95% CI 1.1-2.2; p = 0.035) were revealed as independent predictors of admission to ICU. CONCLUSION: Red blood cell distribution and lymphocytes were the most useful predictors of disease severity identifying HIV infected patients with CAP who required ICU admission.

Tenofovir disoproxil fumarate/emtricitabine plus ritonavir-boosted lopinavir or cobicistat-boosted elvitegravir as a single-tablet regimen for HIV post-exposure prophylaxis.

Objectives: To assess HIV-1 post-exposure prophylaxis (PEP) non-completion at day 28, comparing ritonavir-boosted lopinavir versus cobicistat-boosted elvitegravir as a single-tablet regimen (STR), using tenofovir disoproxil fumarate/emtricitabine with both of these therapies. Methods: A prospective, open, randomized clinical trial was performed. Individuals attending the emergency room due to potential sexual exposure to HIV and who met criteria for PEP were randomized 1:3 into two groups receiving either 400/100 mg of lopinavir/ritonavir (n = 38) or 150/150 mg of elvitegravir/cobicistat (n = 119), with both groups also receiving 245/200 mg of tenofovir disoproxil fumarate/emtricitabine. Five follow-up visits were scheduled at days 1, 10, 28, 90 and 180. The primary endpoint was PEP non-completion at day 28. Secondary endpoints were adherence, adverse effects and rate of seroconversions. Clinical trials.gov number: NCT08431173. Results: Median age was 32 years and 95% were males. PEP non-completion at day 28 was 36% (n = 57), with a trend to be higher in the lopinavir/ritonavir arm [lopinavir/ritonavir 47% (n = 18) versus elvitegravir/cobicistat 33% (n = 39), P = 0.10]. We performed a modified ITT analysis including only those patients who attended on day 1. PEP non-completion in this subgroup was higher in the lopinavir/ritonavir arm than in the elvitegravir/cobicistat arm (33% versus 15%, respectively, P = 0.04). Poor adherence was significantly higher in the lopinavir/ritonavir arm versus the elvitegravir/cobicistat arm (47% versus 9%, respectively, P < 0.0001). Adverse events were reported by 73 patients (59%), and were significantly more common in the lopinavir/ritonavir arm (90% versus 49%, P = 0.0001). A seroconversion was observed in the elvitegravir/cobicistat arm in a patient with multiple exposures before and after PEP. Conclusions: A higher PEP non-completion, poor adherence and adverse events were observed in patients allocated to the lopinavir/ritonavir arm, suggesting that STR elvitegravir/cobicistat is a well-tolerated antiretroviral for PEP.

Safe Reduction in CD4 Cell Count Monitoring in Stable, Virally Suppressed Patients With HIV Infection or HIV/Hepatitis C Virus Coinfection.

BACKGROUND: It has been suggested that routine CD4 cell count monitoring in human immunodeficiency virus (HIV)-monoinfected patients with suppressed viral loads and CD4 cell counts >300 cell/µL could be reduced to annual. HIV/hepatitis C virus (HCV) coinfection is frequent, but evidence supporting similar reductions in CD4 cell count monitoring is lacking for this population. We determined whether CD4 cell count monitoring could be reduced in monoinfected and coinfected patients by estimating the probability of maintaining CD4 cell counts ≥200 cells/µL during continuous HIV suppression. METHODS: The PISCIS Cohort study included data from 14 539 patients aged ≥16 years from 10 hospitals in Catalonia and 2 in the Balearic Islands (Spain) since January 1998. All patients who had at least one period of 6 months of continuous HIV suppression were included in this analysis. Cumulative probabilities with 95% confidence intervals were calculated using the Kaplan-Meier estimator stratified by the initial CD4 cell count at the period of continuous suppression initiation. RESULTS: A total of 8695 patients were included. CD4 cell counts fell to <200 cells/µL in 7.4% patients, and the proportion was lower in patients with an initial count >350 cells/µL (1.8%) and higher in those with an initial count of 200-249 cells/µL (23.1%). CD4 cell counts fell to <200 cells/µL in 5.7% of monoinfected and 11.1% of coinfected patients. Of monoinfected patients with an initial CD4 cell count of 300-349 cells/µL, 95.6% maintained counts ≥200 cells/µL. In the coinfected group with the same initial count, this rate was lower, but 97.6% of coinfected patients with initial counts >350 cells/µL maintained counts ≥200 cells/µL. CONCLUSIONS: From our data, it can be inferred that CD4 cell count monitoring can be safely performed annually in HIV-monoinfected patients with CD4 cell counts >300 cells/µL and HIV/HCV-coinfected patients with counts >350 cells/µL.

Improvement of BMD after Switching from Lopinavir/R Plus Two Nucleos(T)ide Reverse Transcriptase Inhibitors to Lopinavir/R Plus Lamivudine: OLE-LIP Substudy.

OBJECTIVE: To compare 48-week changes in bone mineral density (BMD) and body fat distribution between patients continuing lopinavir/ritonavir and two NRTIs and those switching to lopinavir/ritonavir and lamivudine. METHODS: Substudy of a randomized, open-label, multicenter OLE study was carried out. Adult HIV-infected patients with <50 copies/mL for ≥6 months were randomized (1:1) to continue lopinavir/ritonavir and two NRTIs or switching to lopinavir/ritonavir and lamivudine. Dual-energy X-ray absorptiometry (DXA) was performed at baseline and after 48 weeks to measure bone composition and body fat distribution in both the groups. RESULTS: Forty-one patients (dual-therapy, n = 23; triple-therapy, n = 18) of 239, who received at least one dose of study medication, completed the study: median age, 42 years, 71% male, 73% Caucasian. At week 48, total BMD increased by 1.04% (95% CI, 0.06 to 2.01%) among patients switching to dual-therapy, whereas no significant changes occurred in patients maintaining triple-therapy. Dual-therapy and older age were independently associated with total BMD increase. Among patients discontinuing tenofovir-DF, a significant increase was seen in total BMD (1.43; 95% CI, -0.04 to 2.91) and total hip (1.33%; 95% CI, 0.44 to 2.22%). A non-statistically significant decrease in femoral and spinal BMD was observed in patients who discontinued abacavir and in those continuing triple-therapy. Regarding fat distribution, no significant changes were seen in both the treatment groups. DISCUSSION: BMD increased following switching to lopinavir/ritonavir plus lamivudine in HIV-infected patients on suppressive triple-therapy with lopinavir/ritonavir and two NRTIs including tenofovir-DF.

Acquisition of resistant microorganisms and infections in HIV-infected patients admitted to the ICU.

Whether critically ill human immunodeficiency virus (HIV)-infected patients are at risk of acquiring nosocomial infections and resistant or potentially resistant microorganisms (RPRMs) remains to be clarified. The aim was to compare the acquisition of RPRMs, infections and mortality in critically ill HIV-infected and non-infected patients. An observational, prospective cohort study of patients admitted to a medical intensive care unit (ICU) was undertaken. Swabbing of nares, pharynx and rectum, and culture of respiratory secretions were obtained within 48 h of admission and thrice weekly thereafter. Clinical samples were obtained as deemed necessary by the attending physician. Clinical variables, severity scores on admission and exposures during ICU stay were collected. Logistic regression was used to evaluate ICU mortality. Out of the 969 included patients, 64 (6.6%) were HIV-infected. These patients had a higher Acute Physiology and Chronic Health Evaluation (APACHE) II score on admission (19.5 ± 6.6 vs. 21.1 ± 5.4, p = 0.02), stayed longer in the care unit and were more exposed to several invasive devices and antibiotics. There were no differences in the rate of acquisition of RPRMs and the only difference in ICU-acquired infections was a significantly higher incidence of catheter-related bacteraemia (3% vs. 9%, p = 0.03). The ICU-related mortality was similar in both groups (14% vs. 16%, p = 0.70) and in HIV-infected patients, it tended to be associated with a lower CD4 cell count (p = 0.06). Despite a longer ICU stay, critically ill HIV-infected patients did not show a higher rate of RPRMs acquisition. The rate of ICU-acquired infection was similar between HIV-infected and non-infected patients, except for catheter-related bacteraemia, which was higher in the HIV-infected population. Mortality was similar in both groups.

Differences between HIV-infected and uninfected adults in the contributions of smoking, diabetes and hypertension to acute coronary syndrome: two parallel case-control studies.

OBJECTIVES: The aim of the study was to assess the separate contributions of smoking, diabetes and hypertension to acute coronary syndrome (ACS) in HIV-infected adults relative to uninfected adults. METHODS: Two parallel case-control studies were carried out. In the first study, HIV-positive adults diagnosed with ACS between 1997 and 2009 (HIV+/ACS) were matched for age, gender and known duration of HIV infection with HIV-positive adults without ACS (HIV+/noACS), each individual in the HIV+/ACS group being matched with three individuals in the HIV+/noACS group. In the second study, each individual in the HIV+/ACS group in the first study was matched for age, gender and calendar date of ACS diagnosis with three HIV-negative individuals diagnosed with ACS between 1997 and 2009 (HIV-/ACS). Each individual in the HIV-/ACS group was then matched for age and gender with an HIV-negative adult without ACS (HIV-/noACS). After matching, the ratio of numbers of individuals in the HIV+/ACS, HIV+/noACS, HIV-/ACS and HIV-/noACS groups was therefore 1 : 3 : 3 : 3, respectively. We performed logistic regression analyses to identify risk factors for ACS in each case-control study and calculated population attributable risks (PARs) for smoking, diabetes and hypertension in HIV-positive and HIV-negative individuals. RESULTS: There were 57 subjects in the HIV+/ACS group, 173 in the HIV+/noACS group, 168 in the HIV-/ACS group, and 171 in the HIV-/noACS group. Independent risk factors for ACS were smoking [odds ratio (OR) 4.091; 95% confidence interval (CI) 2.086-8.438; P < 0.0001] and a family history of cardiovascular disease (OR 7.676; 95% CI 1.976-32.168; P = 0.0003) in HIV-positive subjects, and smoking (OR 4.310; 95% CI 2.425-7.853; P < 0.0001), diabetes (OR 5.778; 95% CI 2.393-15.422; P = 0.0002) and hypertension (OR 6.589; 95% CI 3.554-12.700; P < 0.0001) in HIV-negative subjects. PARs for smoking, diabetes and hypertension were 54.35 and 30.58, 6.57 and 17.24, and 9.07 and 38.81% in HIV-positive and HIV-negative individuals, respectively. CONCLUSIONS: The contribution of smoking to ACS in HIV-positive adults was generally greater than the contributions of diabetes and hypertension, and was almost twice as high as that in HIV-negative adults. Development of effective smoking cessation strategies should be prioritized to prevent cardiovascular disease in HIV-positive adults.

Pegylated interferon {alpha}2a plus ribavirin versus pegylated interferon {alpha}2b plus ribavirin for the treatment of chronic hepatitis C in HIV-infected patients.

OBJECTIVES: The two currently available types of pegylated interferon (peg-IFN) used to treat hepatitis C have different pharmacokinetic properties. It is unclear how these differences affect response to therapy. We compared the effectiveness and safety of peg-IFN-alpha2a and peg-IFN-alpha2b, both with ribavirin, against chronic hepatitis C virus (HCV) infection in HIV-infected patients. METHODS: From the GESIDA HIV/HCV cohort, we analysed patients treated with peg-IFN-alpha2a (n = 315) or peg-IFN-alpha2b (n = 242). The primary endpoint was a sustained virological response (SVR). RESULTS: Both groups were well matched in baseline characteristics except for a higher frequency of injection drug users in the peg-IFN-alpha2b group than in the peg-IFN-alpha2a group (85% versus 76%; P = 0.01) and a higher frequency of bridging fibrosis and cirrhosis (F3-F4) in the peg-IFN-alpha2b group than in the peg-IFN-alpha2a group (42% versus 33%; P = 0.04). End-of-treatment response was significantly lower among patients treated with peg-IFN-alpha2b [40% versus 52%; odds ratio (OR), 1.63; 95% confidence interval (95% CI), 1.16-2.29; P < 0.01]. However, no significant differences were found in SVR between patients treated with peg-IFN-alpha2b and those treated with peg-IFN-alpha2a (31% versus 33%; OR, 1.09; 95% CI, 0.75-1.59; P = 0.655). Therapy was interrupted due to adverse events in 33 (14%) patients treated with peg-IFN-alpha2b and 47 (15%) patients treated with peg-IFN-alpha2a. CONCLUSIONS: No differences in effectiveness and safety were found between peg-IFN-alpha2b and peg-IFN-alpha2a for the treatment of chronic HCV infection in HIV-infected patients.

Boceprevir plus pegylated interferon/ribavirin to re-treat hepatitis C virus genotype 1 in HIV-HCV co-infected patients: final results of the Spanish BOC HIV-HCV Study.

INTRODUCTION: Boceprevir (BOC) was one of the first oral inhibitors of hepatitis C virus (HCV) NS3 protease to be developed. This study assessed the safety and efficacy of BOC+pegylated interferon-α2a/ribavirin (PEG-IFN/RBV) in the retreatment of HIV-HCV co-infected patients with HCV genotype 1. METHODS: This was a phase III prospective trial. HIV-HCV (genotype 1) co-infected patients from 16 hospitals in Spain were included. These patients received 4 weeks of PEG-IFN/RBV (lead-in), followed by response-guided therapy with PEG-IFN/RBV plus BOC (a fixed 44 weeks was indicated in the case of cirrhosis). The primary endpoint was the sustained virological response (SVR) rate at 24 weeks post-treatment. Efficacy and safety were evaluated in all patients who received at least one dose of the study drug. RESULTS: From June 2013 to April 2014, 102 patients were enrolled, 98 of whom received at least one treatment dose. Seventy-three percent were male, 34% were cirrhotic, 23% had IL28b CC, 65% had genotype 1a, and 41% were previous null responders. The overall SVR rate was 67%. Previous null-responders and cirrhotic patients had lower SVR rates (57% and 51%, respectively). Seventy-six patients (78%) completed the therapy scheme; the most common reasons for discontinuation were lack of response at week 12 (12 patients) and adverse events (six patients). CONCLUSIONS: Response-guided therapy with BOC in combination with PEG-IFN/RBV led to an overall SVR rate of 67%, but an SVR rate of only 51% in patients with cirrhosis. The therapy was generally well tolerated. Although the current standards of care do not include BOC+PEG-IFN/RBV, the authors believe that this combination can be beneficial in situations where new HCV direct antiviral agent interferon-free therapies are not available yet.

Large de novo deletion in chromosome 12 affecting the PAH, IGF1, ASCL1, and TRA1 genes.

Phenylketonuria is one of the most common genetic diseases in humans, affecting 1 in 10,000 whites. Deletions are generally uncommon in genes in which no long highly homologous segments are present, and in phenylalanine hydroxylase (PAH) deficiency they represent only 5% of cases. We present the case of a girl affected by classical phenylketonuria who has been screened for mutations in the PAH gene. During the molecular study a large de novo deletion has detected in 12qter, including PAH, and the genes for insulin-like growth factor 1 (IGF1), human achaete-scute homolog 1 (ASCL1), and tumor rejection antigen (TRA1). The patient showed phenylketonuria, short stature, and pathological electro-oculography results in both eyes, with high affectation of the relative electrogenesis of the photoreceptor-pigment epithelium complex. She had previously been misdiagnosed as homozygous for the IVS8nt-7A-G mutation, instead of heterozygous for a mutation and a de novo deletion. As a result incorrect genetic counseling had been given. The deletion of the PAH, IGF1, and ASCL1 genes could explain the patient's phenotype corresponding to a contiguous gene syndrome. We stress the relevance of polymorphic marker haplotype analysis and the importance of family study in genetic recessive diseases, such as phenylketonuria, to avoid incorrect diagnosis and genetic counseling.

Vertebral arch tuberculosis in two human immunodeficiency virus-seropositive heroin addicts.

We studied two cases of disseminated tuberculosis with vertebral arch involvement in drug addicts seropositive for human immunodeficiency virus. The first patient developed a paraplegia while he was recovering from a meningeal tuberculosis. On the abdominal plain roentgenogram, the right transverse process of L-2 was absent, and a computed tomographic scan revealed destruction of the right vertebral arch together with a collection in the paravertebral area. The second patient had miliary tuberculosis and complained of lumbar pain. The radiologic findings were similar to those in the first case, but at the L-4 level.

Comparison of metabolic abnormalities 48 weeks after switching from highly active antiretroviral therapy containing a non-nucleoside reverse transcriptase inhibitor to Trizivir versus continued highly active antiretroviral therapy.

Forty patients participating in the TRIZAL study were treated with a non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing regimen before being randomly assigned either to continue their baseline therapy or to switch to a triple nucleoside regimen. No difference was observed in treatment efficacy between the two groups, and total cholesterol was observed to improve significantly in the switch group. Switch maintenance may be an appropriate strategy in patients treated with an NNRTI.

Characteristics of tuberculosis in HIV-infected patients: a case-control study.

To test the hypothesis that HIV infection can modify the clinical characteristics of tuberculosis, 65 consecutive cases of tuberculosis in HIV-seropositive patients diagnosed in Barcelona (Spain) were compared with 65 HIV-seronegative controls matched for age and sex. Thirty of the 65 cases were accepted as AIDS cases (August 1987 Centers for Disease Control criteria) only because of the tuberculosis. Among the cases 54 (83%) were parenteral drug addicts and 88% were males. The tuberculosis was pulmonary or pleural in 62 controls (96%) but in only 25 cases (39%; P less than 0.0001). Lymph nodes were involved in 25 cases (39%) and in none of the controls (P less than 0.0001). Disseminated forms of tuberculosis were present in seven cases (11%) and in no controls (P less than 0.007). Bone, joints and central nervous system involvement were also significantly (P less than 0.05) more frequent in cases. The treatment (isoniazid and rifampin for 6 months plus ethambutol and pyrazinamide during the first 2 months) was always effective. One relapse was detected after a median follow-up of 55 months in cases and none in controls after a median follow-up of 43 months. Twenty-five cases (39%) and 14 controls (22%) developed mild or severe side effects related to the treatment (P less than 0.004). In conclusion, most of the HIV-infected patients with tuberculosis were drug addicts with extrapulmonary or disseminated forms. A short course of treatment (6 or 9 months) may be enough but side effects were frequent.

A prospective study of the risk of tuberculosis among HIV-infected patients.

OBJECTIVE: To evaluate the risk of developing active tuberculosis (TB) in a cohort of HIV-1-infected patients. METHODS: Prospective longitudinal follow-up of 839 HIV-infected patients, of whom 505 (60%) were parenteral drug users and 269 (32%) homosexual men. Tuberculin skin tests were performed at baseline and annually thereafter. Prophylaxis with isoniazid (300 mg daily for 9 months) was offered to those with a positive tuberculin test (induration > or = 5 mm). Diagnosis of TB was accepted if it could be confirmed microbiologically (acid-fast bacilli seen in Ziehl-Neelsen stains or grown in Lowenstein-Jensen cultures) or pathologically (presence of caseating granulomas) and patients had consistent clinical manifestations. RESULTS: Active TB developed in 23 out of the 733 (3.1%) patients with a negative tuberculin skin test after a mean follow-up of 16 +/- 11 months (range, 2-52 months), with an estimated cumulative probability of 1.5 and 7% after 1 and 3 years, respectively (or 2.4 per 100 patient-years). None of the 87 patients with a negative tuberculin test but a positive Multitest developed TB. Conversely, 106 patients had a positive tuberculin skin test (97 at baseline and nine who converted during follow-up). Active TB developed in seven out of the 26 not receiving prophylaxis or in whom prophylaxis had to be discontinued (16.2 per 100 patient-years), in four out of 61 patients 3-27 months after having completed 9 months of prophylaxis with isoniazid (8.9 per 100 patient-years) and in none of the 19 still receiving isoniazid. When TB was diagnosed, the mean CD4 lymphocyte count of the 34 patients who developed it during follow-up was 77 +/- 103 x 10(6)/l (range, 1-400 x 10(6)/l). CONCLUSIONS: Among HIV-infected patients in whom the tuberculin skin test is negative, the risk of developing active TB is sufficient to consider prophylaxis if the CD4 count falls below 400 x 10(6)/l, at least in those patients with skin anergy living in high-risk geographical areas such as Spain. When the tuberculin skin test was positive, isoniazid (9 months) provided a 45% protection beyond the period of its administration.

PIP: This study sought to evaluate the risk of developing active tuberculosis (TB) in a cohort of HIV-1-infected patients. A prospective longitudinal follow-up was carried out on 839 HIV-infected patients, of whom 505 (60%) were parenteral drug users and 269 (32%) were homosexual men. Tuberculin skin tests were performed at baseline and annually thereafter. Prophylaxis with isoniazid (300 mg daily for 9 months) was offered to those with a positive tuberculin test (induration or= 5 mm.). Diagnosis of TB was accepted if it could be confirmed microbiologically (acid-fast bacilli seen in Ziehl-Neelsen stains or grown in Lowenstein-Jensen cultures) or pathologically (presence of caseating granulomas) and patients had consistent clinical manifestations. Active TB developed in 23 of the 733 (3.1%) patients with a negative tuberculin skin test after a mean follow-up of 16 +or- 11 months (range, 2-52 months), with an estimated cumulative probability of 1.5 and 7% after 1 and 3 years, respectively (or 2.4 per 100 patient-years). None of the 87 patients with a negative tuberculin test, but a positive Multitest, developed TB. Conversely, 106 patients had a positive tuberculin skin test (97 at baseline and 9 who converted during follow-up). Active TB developed in 7 of the 26 not receiving prophylaxis or in whom prophylaxis had to be discontinued (16.2 per 100 patient-years), in 4 of 61 patients 3-27 months after having completed 9 months of prophylaxis with isoniazid (8.9 per 100 patient-years), and in none of the 19 still receiving isoniazid. When TB was diagnosed, the mean CD4 lymphocyte count of the 34 patients who developed it during follow-up was 77 +or- 103 x 106/L (range, 1-400 x 106/L). Among HIV-infected patients in whom the tuberculin skin test is negative, the risk of developing active TB is sufficient to consider prophylaxis if the CD4 count falls below 400 x 106/L, at least in those patients with skin anergy living in high-risk geographical areas such as Spain. When the tuberculin skin test was positive, isoniazid (9 months) provided a 45% protection beyond the period of its administration.

Efficacy of octreotide in the management of chronic diarrhoea in AIDS.

Patients with HIV infection were studied to assess the efficacy of octreotide, a somatostatin analogue, in the long-term management of refractory diarrhoea. Dosage of subcutaneous octreotide was increased progressively at 48 h intervals from 150 to 300, 750 and 1500 micrograms/day according to response. Twenty-nine patients, 21 with Cryptosporidium enteritis, one with Isospora belli enteritis and seven with no identifiable pathogen were selected for the study; four of these were excluded from the study because of death during the first month (two cases), abdominal pain and acute pancreatitis (one case each). Twenty-five patients were evaluable for response. Ten patients (four with Cryptosporidium enteritis, five without an identifiable pathogen and one with I. belli enteritis) achieved a complete response (40%) and nine cases (all with cryptosporidial enteritis) had a partial response (36%). Patients with higher weight and Karnofsky performance status and non-cryptosporidial enteritis had a better response to treatment. Mean durations of treatment and response were 4.2 +/- 4.2 and 4.4 +/- 4.5 months, respectively. In the absence of specific agents for cryptosporidial enteritis and HIV enteropathy, octreotide was found to be useful in the management of chronic diarrhoea in AIDS patients.

Lymphoid tissue viral burden and duration of viral suppression in plasma.

OBJECTIVES: To assess virological response in lymphoid tissue and its impact on the durability of response in plasma in HIV-1-infected persons who achieved sustained suppression of plasma viraemia with different antiretroviral regimens. METHODS: Consecutive patients on first-line antiretroviral therapy were included if they had a plasma HIV-1 RNA viraemia < 20 copies/ml within the last 6 months and tonsillar tissue accessible for biopsy. First-line therapy contained two nucleoside analogues: alone (2NRTI group, n = 3); plus a HIV-1 protease inhibitor (PI group, n = 11) or plus nevirapine (NVP group; n = 16). Patients were followed until virus was detectable in plasma, they changed therapy or were lost to follow-up. RESULTS: Tonsillar HIV-1 RNA could be detected (> 100 copies/mg) in 10 patients: one in the PI group (9%), six (38%) in the NVP group and in all three patients in the 2NRTI group. Primary resistance mutations could be detected in only 2 of these 10 patients. After a median of 9 months after the biopsies, viral suppression in plasma had failed in 6 of these 10 patients whereas failure had only occurred in 1 out of 20 with initially undetectable viral load in lymphoid tissue (P = 0.01; log rank test). CONCLUSIONS: In patients with sustained viral suppression in plasma, triple therapy including a HIV-1 protease inhibitor was more potent than triple therapy containing nevirapine or dual therapy with nucleoside analogues to reduce viral burden in lymphoid tissue. A worse response in lymphoid tissue could not be explained by local selection of resistance and was associated with a less durable virological response in plasma.

Primary prophylaxis for Pneumocystis carinii pneumonia: a randomized trial comparing cotrimoxazole, aerosolized pentamidine and dapsone plus pyrimethamine.

OBJECTIVE: To compare the efficacy and tolerance of monthly aerosolized pentamidine versus cotrimoxazole versus dapsone plus pyrimethamine to prevent the initial episodes of Pneumocystis carinii pneumonia (PCP) in HIV-infected patients. DESIGN: An open randomized clinical trial. PATIENTS AND METHODS: HIV-infected patients (n = 331) with CD4 cell counts < 200 x 10(6)/l or with AIDS but without a history of PCP or cerebral toxoplasmosis (CT) were randomized to receive pentamidine (300 mg every 4 weeks), cotrimoxazole (160/800 mg 3 days a week) or dapsone plus pyrimethamine (100 and 25 mg weekly). If immunoglobulin G (IgG) antibodies to Toxoplasma were present, patients in the first two groups were randomized further to 25 mg pyrimethamine per week or to no treatment. RESULTS: The mean follow-up was 313 days (range, 30-670 days). The three groups were homogeneous for age, sex, risk group for HIV infection, initial CD4 cell count and mean follow-up. PCP developed in 16 patients, with an estimated cumulative probability of 5.3% at 1 year of follow-up. The PCP rate per year of observation, using an intention-to-treat analysis, was 5.6% [95% confidence interval (CI), 0.9-10.3], 3% (95% CI, 0-6.3) and 8.3% (95% CI, 2.8-13.8) in the groups treated with pentamidine, cotrimoxazole and dapsone plus pyrimethamine, respectively (P > 0.05). Moderate or severe side-effects were observed in one patient on pentamidine, 10 on cotrimoxazole and nine on dapsone plus pyrimethamine (P < 0.05); the study drug had to be discontinued in no, 10 and six patients, respectively (P < 0.05). Neither cotrimoxazole alone nor pyrimethamine combined with dapsone or cotrimoxazole prevented initial episodes of toxoplasmosis among patients with IgG antibodies to Toxoplasma gondii. CONCLUSIONS: Low-dose thrice-weekly cotrimoxazole or weekly dapsone plus pyrimethamine was not significantly worse (differences > 15% would have been detected with 90% certainty) than monthly aerosolized pentamidine in preventing a first episode of PCP in patients at high risk, but aerosolized pentamidine was better tolerated.

Central nervous system toxoplasmosis in AIDS patients: efficacy of an intermittent maintenance therapy.

Fifty-five episodes of central nervous system (CNS) toxoplasmosis developing in 43 of the 329 AIDS cases seen at our institution were diagnosed during a 34-month period and were prospectively studied. Acute episodes were treated with a pyrimethamine/sulfadiazine (P/S) combination for a mean of 21 days. Because of a previously known major allergy to sulfonamides, three episodes were treated with clindamycin instead of sulphadiazine. In those patients who accepted maintenance therapy, a combination of P/S or pyrimethamine and clindamycin (P/C) was administered 2 days per week. Thirty-six patients (83.7%) survived the first episode. Four of these 36 were lost to further study. Six of the 12 (50%) who decided not to undergo maintenance therapy relapsed (mean follow-up: 12 months). Fourteen patients were given P/S and none relapsed while they were on maintenance therapy (mean follow-up: 10.3 months). Six patients received an intermittent maintenance treatment with P/C and one relapsed 2 months after starting the maintenance therapy (mean follow-up: 13.7 months). We conclude that an intermittent (2 days per week) maintenance treatment for CNS toxoplasmosis with P/S was effective in preventing relapses, although prospective randomized studies remain to be done.

Hepatotoxicity in HIV-1-infected patients receiving nevirapine-containing antiretroviral therapy.

OBJECTIVES: To assess the incidence and risk factors for hepatotoxicity associated with nevirapine. DESIGN: A prospective cohort study in a teaching and referral hospital involving all consecutive patients who were prescribed a nevirapine-containing antiretroviral regimen between September 1997 and May 2000. METHOD: Cutaneous and hepatic adverse reactions and clinical hepatitis were assessed. Blood analysis including plasma HIV-1 RNA CD4 cell counts, liver chemistry tests, and serology for hepatitis B and C viruses. Hepatotoxicity was defined as an increase of at least threefold in serum alanine aminotransferase or aspartate aminotransferase levels compared with baseline values. RESULTS: Of a total of 610 patients, 82 (13.4%) were antiretroviral naive when commencing nevirapine, and 46.2 and 8.9% were coinfected with hepatitis C and B viruses, respectively. Median duration of exposure to nevirapine was 8.7 months (interquartile range 3.4--14.3). Hepatotoxicity developed in 76 (12.5%), an incidence of 13.1/100 person-years. Kaplan--Meier estimated incidence of hepatotoxicity at 3, 6 and 12 months was 3.7, 9.7 and 20.1%, respectively. In seven (1.1%) patients, hepatotoxicity was associated with clinical hepatitis, which was reversible upon discontinuation of therapy. Multivariate analysis identified the duration of prior exposure to antiretroviral drugs, hepatitis C virus, and higher baseline levels of alanine aminotransferase as independent risk factors for hepatotoxicity. CONCLUSIONS: Hepatotoxicity but not clinical hepatitis was common in HIV-1-infected patients receiving nevirapine-containing regimens and the incidence steadily increased over time. Prolonged exposure to any antiretroviral therapy, coinfection with hepatitis C virus and abnormal baseline levels of alanine aminotransferase identified patients at a higher risk.