Highly active antiretroviral therapy failure and protease and reverse transcriptase human immunodeficiency virus type 1 gene mutations.
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Anti-HIV Agents↗
Biomedical subjects
G Angarano
Publications and source records attributed to G Angarano.
Longitudinal human immunodeficiency virus type 1 load in the italian seroconversion study: correlates and temporal trends of virus load.
A prospective study of 149 human immunodeficiency virus type 1 (HIV-1) seroconverters was conducted to describe trends and correlates of HIV-1 load after seroconversion and over time. HIV-1 load was quantified from frozen sera by reverse transcriptase-polymerase chain reaction. High early virus load was associated with lower CD4 cell counts and male sex but not with age at seroconversion or injection drug use. Early virus load predicted progression to clinical AIDS and AIDS/<200 CD4 cells/microL. Virus load exhibited a decline of 52% by 18 months after seroconversion then increased 23% annually (95% confidence interval, 13%-33%). Men and those developing AIDS during follow-up had higher virus loads over the course of disease. Persons who developed AIDS had a steeper virus load slope than those who were AIDS-free (P=.01). In long-term follow-up, virus load exhibited a gradual and sustained increase over time. Virus load and annual increase are strong predictors of disease progression.
Acquired Immunodeficiency Syndrome↗
Efficacy of protease inhibitor-based anti-retroviral therapy in severe HIV-associated thrombocytopenia unresponsive to AZT.
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Acquired Immunodeficiency Syndrome↗
Reduced concentrations of HIV-RNA and TNF-alpha coexist in CSF of AIDS patients with progressive multifocal leukoencephalopathy.
OBJECTIVES: To confirm reduced human immunodeficiency virus type-1 (HIV-1) burden in the CSF of patients with progressive multifocal leukoencephalopathy (PML) and to verify whether this viral load coincides with the absence of inflammatory changes in the CSF. METHODS: Paired CSF and plasma samples from 17 patients with PML, 26 with non-PML cerebral opportunistic infections, nine with HIV-1 leukoencephalopathy (HIVE), and 12 neurologically asymptomatic AIDS patients were subjected to HIV-RNA titration. Tumour necrosis factor (TNF)-alpha was also measured and the CSF albumin: serum albumin ratio (Q(Alb)) was calculated. RESULTS: The CSF HIV-1 burden of patients with PML did not differ from that of neurologically asymptomatic patients (p=0.21), but was significantly lower than CSF burden of the remaining patients (non-PML opportunistic infections, p<0.001; HIVE, p<0.001). Q(Alb) was normal for all neurologically asymptomatic patients, for 86.6% patients with PML, and 62.5% patients with HIVE (p=0.09). Q(Alb) was altered in 91.6% patients with non-PML opportunistic infections. TNF-alpha in CSF was higher in patients with non-PML opportunistic infections (p<0.001) and those with HIVE (p<0.001) than in patients with PML who consistently had TNF-alpha concentrations<10 pg/ml. CONCLUSIONS: These results, while indicating a reduced HIV replication in CSF of patients with PML which might serve as a disease marker, emphasise the increased CSF HIV-RNA concentration in patients with HIVE and patients with non-PML opportunistic infections. Low concentrations of HIV-RNA in CSF coincide with reduced TNF-alpha concentrations, possibly due to particular features of PML compared with other opportunistic infections as it develops without detectable inflammatory changes in the CSF.
Acquired Immunodeficiency Syndrome↗
Reproductive choice in individuals HIV-1 infected in south eastern Italy.
OBJECTIVE: To evaluate the impact of counseling on reproductive choices in seropositive women in South-Eastern Italy. SETTING: University Hospital, Apulia region, South-Eastern Italy, tertiary referral center for high risk obstetrics and infectious diseases. METHODS: Between March 1985 and December 1996, two hundred and twenty-five HIV-infected women, receiving treatment at our clinic for infectious diseases were enrolled. They were all regularly given treatment and counseling and their sexual partners, if negative, tested for HIV-1 antibodies. Their reproductive choices and their attitude toward pregnancy were recorded and analyzed. RESULTS: Seventy-six pregnancies were observed during this period in 76 women. Twenty-one of these women (27.7%) decided to terminate the pregnancy. Women that were intravenous drug users or with a longer history of known seropositivity were more likely to have a termination. A decreasing trend in the request of abortion was observed with time. CONCLUSIONS: The data show that the scenario of HIV-infected women is changing in our setting. As a consequence, many seropositive women deliberately choose to have a pregnancy and factors different from those we expect to be modified by the counseling influence their reproductive choice. They should be taken into account in the management of these women before and during pregnancy.
Abortion, Induced↗
Phenotypic patterns of HIV-1 clonal populations during highly active antiretroviral therapy (HAART).
Several studies have demonstrated that during HIV-1 infection many different viral clones may co-exist in the same individual. These clones may differ regarding their biological phenotype and may influence both the natural history of infection and the clinical response to antiretroviral therapy. The aim of the present study was to investigate the influences of combination therapies including protease inhibitors (HAART) on the phenotypical pattern of HIV-1 biological clones in peripheral blood mononuclear cells. Viral isolation and biological characterisation of bulk isolates and clonal viral isolates were performed on two AIDS patients, before and after three months of antiretroviral therapy. A decrease of viral load in plasma specimens in association with a change of clonal composition during antiretroviral therapy was observed in both patients during treatment. Before therapy both of the patients had a syncytium inducing (SI) bulk isolate and the majority of the biological clones were characterised as SI. After treatment, the bulk isolates were still SI in both cases, but the majority of biological clones were characterised as non-syncytium inducing (NSI). These results suggest that HIV clonal composition and relative phenotypic pattern undergo different changes not only during the natural course of HIV infection but also while patients are on antiretroviral combination therapy.
Anti-HIV Agents↗
Coming therapies: adefovir.
Adefovir dipivoxil, an acyclic nucleotide phosphonate analogue, demonstrates a potent and sustained antiviral activity. Its long half-life allows once daily administration and due to the observed reduction in L-carnitine plasma levels, supplementation with L-carnitine is required. Clinical evidence indicates adefovir dipivoxil can be used as first-line therapy. In addition, due to the sensitivity of drug resistant strains to adefovir dipivoxil, it also has a role in second-line or multi-drug salvage regimens. Adefovir dipivoxil is safe and well tolerated for only short periods of treatment.
Adenine↗
Comparison of once and twice daily dosing of didanosine in combination with stavudine for the treatment of HIV-1 infection. AI 454-146 Team.
OBJECTIVE: To compare the antiviral activity, safety and tolerability of didanosine dosed once and twice daily when administered in combination with stavudine dosed twice daily in human immunodeficiency virus type 1 (HIV-1)-infected individuals with little or no previous exposure to antiretroviral drugs. DESIGN: Comparative, multicentre, randomized, open-label, short-term study. PATIENTS AND METHODS: Eighty-four HIV-1-infected adults with qualifying baseline CD4 cell counts of 200 to 500 cells/mm3 were included in the study. Of these, 43 patients received once daily didanosine plus twice daily stavudine (group A) and 41 subjects received twice daily didanosine plus twice daily stavudine (group B). The primary efficacy analysis used was the time-averaged difference (TAD) between treatment regimens of variations in plasma HIV-1 RNA levels from baseline over the first 12 weeks of therapy. Plasma HIV-1 RNA levels, CD4 cell counts and adverse events were monitored. RESULTS: At week 12, median HIV-1 RNA variations were -1.18 log10 copies/ml in group A and -0.88 log10 copies/ml in group B. For patients who were followed up to week 24, median variations of HIV-1 RNA levels from baseline were -1.21 log10 copies/ml in group A and -0.78 log10 copies/ml in group B. The TAD between the two treatment groups for variations from baseline plasma HIV-1 RNA levels over the first 12 weeks was 0.10 log10 copies/ml (95% confidence interval, -0.19 to 0.40), indicating equivalence. CONCLUSION: Once daily didanosine plus twice daily stavudine and twice daily didanosine plus twice daily stavudine are equally effective in reducing plasma HIV-1 RNA levels and increasing CD4 cell counts. Both regimens are safe and well tolerated.
Adult↗
Neurological disorders during HIV-1 infection correlate with viral load in cerebrospinal fluid but not with virus phenotype.
OBJECTIVES: To verify the compartmentalization of HIV-1 within the central nervous system (CNS) and to define whether viral phenotype of HIV-1 isolates from cerebrospinal fluid (CSF) samples and CSF viral load correlate with the presence and type of neurological disorders. METHODS: A total of 33 HIV-1-infected patients with and without neurological disorders were included in the study. HIV-1 isolation from paired CSF and peripheral blood mononuclear cell (PBMC) samples was attempted by a standard cocultivation technique; the biological phenotype of HIV-1 isolates was assessed by the MT-2 cell assay. CSF and plasma HIV-RNA levels were measured by a quantitative reverse transcripase-polymerase chain reaction. RESULTS: The rate of HIV-1 isolation from CSF and PBMC was 66% (22 isolates) and 85% (28 isolates), respectively. Seventeen out of 22 (77%) CSF HIV-1 isolates were characterized as non-syncytium-inducing, and 15 out of 28 (68%) isolates from PBMC were typed as syncytium-inducing (SI). The presence of SI isolates in CSF was limited to patients with HIV-1-, cytomegalovirus- or JC virus-related disorders and was often associated with high levels of HIV-1 RNA in the CSF. DISCUSSION: Our results demonstrate a correlation between high levels of HIV RNA in CSF and the presence of neurological disorders thus indicating a possible role for HIV-1 RNA in the CSF as a biological marker of neurological disease. The finding of viruses with a different phenotype in paired CSF and PBMC indicates that HIV-1 may evolve differently in the brain and in the blood. This suggests compartmentalization of HIV-1 within the CNS.
CD4 Lymphocyte Count↗
Measurement of viral sequences in cerebrospinal fluid of AIDS patients with cerebral white-matter lesions using polymerase chain reaction.
OBJECTIVES: To optimize the use of polymerase chain reaction (PCR) on cerebrospinal fluid (CSF) for the evaluation of central nervous system (CNS) white-matter lesions that along with clinical findings and magnetic resonance imaging (MRI) can allow a definite diagnosis to be made; also to evaluate treatment with zidovudine plus foscarnet. DESIGN AND METHODS: Fifteen AIDS patients with uncertain CNS white-matter lesions were identified. HIV-1 RNA, cytomegalovirus (CMV) and JC virus (JCV) DNA were measured in a total of 29 CSF samples. The results were correlated with clinical and MRI findings and treatment with zidovudine plus foscarnet was evaluated. RESULTS: Four and five out of 15 patients with CMV DNA > or = 1 : 625 and JCV DNA > or = 10(3) copies/microl detected in the CSF were diagnosed with CMV and progressive multifocal leukoencephalopathy (PML), respectively. Six patients who were CMV/JCV-negative with the highest levels of HIV RNA (median, 6.87 log10 copies/ml) in CSF were considered as having HIV-1 encephalitis. Neurological symptoms were non-supportive for diagnosis as was MRI in 11 out of 15 patients. Nine patients completed a 21-day course of zidovudine plus foscarnet. HIV RNA decreased irrespective of neurological diagnosis. All three HIV-1 encephalitis patients and two out of three patients with CMV leukoencephalopathy improved. In these two latter patients, relief of clinical symptoms coincided with decreased CMV DNA. JCV DNA remained unchanged and all three PML patients deteriorated. CONCLUSIONS: Measurement of CSF viral sequences supports the diagnosis of CNS white-matter lesions in AIDS patients. While effective therapy for PML remains elusive, treatment including zidovudine plus foscarnet may be a promising option for HIV-1 and CMV-related manifestations.
AIDS Dementia Complex↗
Itraconazole as maintenance therapy for visceral leishmaniasis in HIV-infected patients.
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AIDS-Related Opportunistic Infections↗
Diffuse necrotic hepatic lesions due to visceral leishmaniasis in AIDS.
A rare case of an AIDS patient who developed scattered necrotic involvement of the liver caused by Leishmania infantum is described. Of interest, marked splenomegaly, hypergammaglobulinemia and serum anti-Leishmania antibodies were absent and an incomplete response to therapy was observed. Diagnosis of visceral leishmaniasis (VL) was achieved by the demonstration of numerous amastigotes in both hepatocytes and macrophages on liver biopsy. Hepatic necrotic lesions, which when extensive could lead to acute hepatic failure, possibly reflect an atypical manifestation of liver involvement caused by L. infantum and depend on the immunological impairment which characterizes AIDS patients, thus preventing the formation of granulomas. Our observation confirms that VL can manifest atypical aspects in HIV-positive patients depending on the degree of the immunodeficiency. The frequency and severity of this pathology accounts for the need to list VL among AIDS-defining conditions.
AIDS-Related Opportunistic Infections↗
Randomized trial of trimethoprim-sulfamethoxazole versus pyrimethamine-sulfadiazine for therapy of toxoplasmic encephalitis in patients with AIDS. Italian Collaborative Study Group.
The aim of the present pilot study was to compare the efficacy and safety of trimethoprim (TMP) and sulfamethoxazole (SMX) with those of the standard therapy pyrimethamine (P)-sulfadiazine (S) for the treatment of toxoplasmic encephalitis in patients with AIDS. This was a pilot, multicenter, randomized, and prospective study. Patients were randomly assigned to receive TMP (10 mg/kg of body weight/day) and SMX (50 mg/kg/day) or P (50 mg daily) and S (60 mg/kg/day) as acute therapy (for 4 weeks) and then as maintenance therapy for 3 months at half of the original dosage. Seventy-seven patients were enrolled and randomized to the study: 40 patients were treated with TMP-SMX and 37 were treated with P-S. There was no statistically significant difference in clinical efficacy during acute therapy. In contrast, patients randomized to TMP-SMX appeared more likely to achieve a complete radiologic response after acute therapy. Adverse reactions were significantly more frequent in patients treated with P-S, and skin rash was the most common adverse event noted in these patients. In conclusion, the results of the study suggest that TMP-SMX appears to be a valuable alternative to P-S, in particular in patients with opportunistic bacterial infections.
AIDS-Related Opportunistic Infections↗
Localised 1H-MR spectroscopy for metabolic characterisation of diffuse and focal brain lesions in patients infected with HIV.
OBJECTIVES: To evaluate the role of proton MR spectroscopy (1H-MRS) in detecting metabolic changes in diffuse or focal lesions in the brain of patients infected with HIV. METHODS: Sixty HIV seropositive patients (25 with HIV related encephalopathies, 20 with toxoplasmosis, eight with progressive multifocal leukoencephalopathies (PMLs), and seven with lymphomas) and 22 HIV seronegative neurological controls were examined with a combined MRI and 1H-MRS technique using a Siemens 1.5 Tesla Magnetom. Spectra (Spin Echo sequence, TE 135 ms) were acquired by single voxel, localised on focal lesions in toxoplasmosis, PML, lymphomas, and HIV encephalopathies and on the centrum semiovale of neurological controls. Choline (Cho), creatine (Cr), N-acetyl aspartate (NAA), lactate, and lipids were evaluated in each spectrum and NAA/Cr, NAA/Cho, and Cho/Cr ratios were calculated. RESULTS: A significant decrease in NAA/Cr and NAA/Cho ratios were found in all HIV diagnostic groups in comparison with neurological controls (p<0.003), suggesting neuronal or axonal damage independent of brain lesion aetiology. However, the NAA/Cr ratio was significantly lower in PML and lymphomas than in HIV encephalopathies (p<0.02) and toxoplasmosis (p<0.05). HIV encephalopathies, lymphomas, and toxoplasmosis showed a significant increase in the Cho/Cr ratio in comparison with neurological controls (p<0.03) without between group differences. The presence of a lipid signal was more frequent in lymphomas (71%) than in other HIV groups (Fisher's test, p=0.00003). The presence of mobile lipid resonance together with a high Cho/Cr ratio in lymphomas may be related to an increased membrane synthesis and turnover in tumour cells. A lactate signal (marker of inflammatory reaction), was found in all but one patient with PML lesions (75%), but had a lower incidence in the other HIV diagnostic groups (Fisher's test, p=0.00024). CONCLUSION: 1H-MRS shows a high sensitivity in detecting brain involvement in HIV related diseases, but a poor specificity in differential diagnosis of HIV brain lesions. Nevertheless, the homogeneous metabolic pattern that characterises PML suggests the usefulness of 1H-MRS as an adjunct to MRI in differentiating CNS white matter lesions, such as HIV encephalopathies, from PML.
AIDS Dementia Complex↗
Drug-resistant tuberculosis in human immunodeficiency virus infected persons in Italy. The Italian Drug-Resistant Tuberculosis Study Group.
OBJECTIVE: To describe the prevalence and epidemiological-clinical characteristics of tuberculosis (TB) resistance to first-line drugs in Italian human immunodeficiency virus (HIV)-infected subjects. DESIGN: Prospective, observational multicenter (25 Centers of Infectious Diseases) study. Mycobacterium tuberculosis strains from 167 HIV co-infected subjects with TB (149 new cases, 18 relapses) were tested at a central laboratory for susceptibility to rifampin (R), isoniazid (H), pyrazinamide (Z), ethambutol (E) and streptomycin (S) and for DNA fingerprint type. Drug susceptibility results were related to patients' epidemiological, clinical and laboratory features. RESULTS: Drug resistance patterns among new TB cases were as follows: R = 1%, Z = 6%, S = 8%, H + S = 3%, S + Z = 4%. TB resistant to at least R + H (MDR-TB) was detected in 36% of new cases due to an MDR-TB outbreak which was the largest thus far in Europe, involving 7/25 participating institutions, and was demonstrated by conventional and molecular epidemiology evidence. With multivariate analysis, MDR-TB was associated with hospital exposure to MDR-TB (OR = 39.3, P < 0.001) and previous use of anti-TB drugs (OR = 9.8, P = 0.008). CONCLUSION: As drug-resistant tuberculosis in Italy is thus far relatively scarce, detection of a large MDR-TB epidemic among HIV-infected subjects was alarming. Aggressive control measures are urgently needed to prevent the spread of MDR-TB throughout the country and among the general population.
AIDS-Related Opportunistic Infections↗
Clinical aspects of antiretroviral resistance.
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Anti-HIV Agents↗
Biological correlates of HIV-1 heterosexual transmission.
OBJECTIVES: To study the role of HIV-1 biological phenotype, viral load and neutralizing antibodies in male-to-female heterosexual transmission of HIV-1. METHODS: Seven transmitting and seven non-transmitting HIV-1-seropositive heterosexual male index cases were included in the present study. All couples had engaged in unprotected sex for a period of over 1 year. Transmission was defined by the seroconversion of the female sexual partner. Virus isolates were tested in MT-2 cells for replication and syncytia induction. HIV-1 RNA plasma load was measured by the branched DNA technique. Serum neutralizing activity to primary HIV-1 isolates was tested by using peripheral blood mononuclear cells (PBMC) as target cells. RESULTS: Non-transmitting index cases had a lower HIV-1 RNA concentration in plasma than transmitting index cases. Non-transmitting index cases also tended to have serum neutralizing activity with broad specificity and to have viruses with low replicative capacity, as characterized by 50% infectious dose titres in PBMC and by the lack of MT-2 tropism. CONCLUSIONS: The results indicate that plasma viral-RNA load is a marker for transmission. Moreover, an interplay between the host immune response and viral replication may modulate the level of viral load and thereby influence HIV-1 transmission.
Cell Line↗
How many HIV-infected individuals may be defined as long-term nonprogressors? A report from the Italian Seroconversion Study. Italian Seroconversion Study Group (ISS)
We prospectively examined a cohort of HIV-positive persons with an accurately estimated date of HIV seroconversion who were infected through injecting drug use or sexual contact to estimate the proportion of long-term nonprogressors (LTNP), considering four definitions of LTNPs. We also evaluated whether factors such as gender, age, and HIV-exposure category were associated with being LTNP; we determined the overlap among the definitions and compared the CD4 and CD8 counts and the CD4/CD8 decline among LTNPs and "moderate" and "fast" progressors. Of the 528 persons selected for analysis, 2 to 4% were considered LTNPs, depending on the definition. The proportion of LTNPs varied by definition, and there was little overlap among definitions. The LTNPs did not appear to differ from "moderate" and "fast" progressors with regard to main demographic characteristics, and they showed a better trend of immunological parameters, appearing to have a slower progression rather than a permanently arrested infection.
Adolescent↗