ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

BackgroundTherapy with HIV protease inhibitors (PI) has been associated with hyperglycemia, hyperlipidemia and changes in body composition. It is unclear whether these adverse effects are drug related, involve an interaction with the host response to HIV or reflect changes in body composition.MethodsIndinavir 800 mg twice daily was given to 10 HIV-seronegative healthy men to distinguish direct metabolic effects of a PI from those related to HIV infection. Fasting glucose and insulin, lipid and lipoprotein profiles, oral glucose tolerance (OGTT), insulin sensitivity by hyperinsulinemic euglycemic clamp, and body composition were measured prior to and after 4 weeks of indinavir therapy.ResultsFasting glucose (4.9 ± 0.1 versus 5.2 ± 0.2 mmol/l;P= 0.05) insulin concentrations (61.7 ± 12.2 versus 83.9 ± 12.2 pmol/l;P< 0.05), insulin : glucose ratio (12.6 ± 1.7 versus 15.9 ± 1.9 pmol/mmol;P< 0.05) and insulin resistance index by homeostasis model assessment (1.9 ± 0.3 versus 2.8 ± 0.5;P< 0.05) all increased significantly. During OGTT, 2 h glucose (5.1 ± 0.4 versus 6.5 ± 0.6 mmol/l;P< 0.05) and insulin levels (223.1 ± 48.8 versus 390.3 ± 108.8 pmol/l;P=0.05) also increased significantly. Insulin-mediated glucose disposal decreased significantly (10.4 ± 1.4 versus 8.6 ± 1.2 mg/kg ⋅ min per μU/ml insulin; 95% confidence interval 0.6–3.0;P< 0.01). There was no significant change in lipoprotein, triglycerides or free fatty acid levels. There was a small loss of total body fat (15.8 ± 1.4 versus 15.2 ± 1.4 kg;P= 0.01) by X-ray absorptiometry without significant changes in weight, waist : hip ratio, and visceral or subcutaneous adipose tissue by computed tomography.ConclusionsIn the absence of HIV infection, treatment with indinavir for 4 weeks causes insulin resistance independent of increases in visceral adipose tissue or lipid and lipoprotein levels.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

SummaryResults from the first phase III efficacy trial of an HIV vaccine will be available within the next 2-3 years. Thus, it is imperative to start planning now to address how any effective vaccines should be used. In the absence of definitive information on the characteristics of the first generation of HIV vaccines, the following assumptions were made: the vaccine will (i) have only low to moderate efficacy (on the order of 50%); (ii) not be inexpensive (on the order of 10 to 30 US $ per dose); (iii) require multiple doses; and, (iv) at least initially, be available in limited quantities. A vaccine with that profile would not be suitable for general use in all countries, and it might have to be initially targeted to populations at higher risk of HIV infection. These populations will differ from region to region, according to the epidemiological situation. In most high and middle income countries potential target groups for an initial HIV immunization programme would include intravenous drug users, gay men, commercial sex workers, and high-risk heterosexuals, as well as healthcare workers exposed to blood. In sub-Saharan Africa, future HIV immunization programmes might include larger segments of the population. In order to plan future vaccination programmes it is important to estimate the need (size of target population) and the demand (uptake in target populations) for future HIV vaccines. In addition to the public sector demand for an HIV vaccine (to be used in public health programmes), there will also be a private sector demand driven by the willingness and ability of individuals and employers to pay for the vaccine. HIV vaccines would need to be delivered as part of comprehensive HIV prevention packages, including behavioral and health promotion interventions. This would be especially important with vaccines of moderate efficacy, in order to prevent increased risk behavior among vaccine recipients. To avoid false expectations, the vaccine message would need to be recast as part of the total prevention strategy, rather than the ‘‘magic bullet’’ that people have come to expect. Initial deployment of HIV vaccines could proceed through targeted vaccination campaigns, drawing from experience with other vaccines. These campaigns would be complex and expensive, and would require full participation and collaboration from all levels of the community, as well as considerable strengthening of the infrastructures required for vaccine delivery. Current candidate vaccines in phase III trials may not be appropriate for much of Africa and South Asia, two areas most in need of an HIV vaccine. Credible international efforts (`‘push and pull’’ mechanisms) are needed to create incentives for the industry to develop vaccines for these regions. Feasible financing mechanisms may have to be established to cover the cost of production and delivery of vaccines, in order to ensure equitable access to HIV vaccines around the world. In parallel to the deployment of the initial vaccine, additional bridging studies and effectiveness trials may be needed to expand vaccine use. Research should also continue at an increased pace to develop new generations of more effective vaccines, especially vaccines appropriate to Africa. Achieving these goals will require real political commitment from government and international organizations, to be materialized in specific actions and budget allocations. The daunting challenge of making future effective vaccines accessible to all populations in need will require a sustained collaborative effort on the part of all parties involved.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

BackgroundIntegration of the HIV genome by integrase is absolutely required for productive infection.ObjectiveTo determine the role of natural selection on HIV integrase biology.DesignTo study the activities of HIV integrases from a limited panel of North American clinical isolates from HIV-infected patients and to compare these proteins with integrases from two laboratory adapted reference strains (HIVIIIRFand HIVNL4−−3).MethodsHIV was isolated and the particle-associated RNA was reverse transcribed and sequenced. Replication kinetics of molecularly cloned viruses containing each variant integrase were studied in tissue culture. The mutant integrase proteins were expressed, purified and specific activities of the enzymes were derived for both 3′ end-processing and disintegration reactions.ResultsDespite 3–5% variability in integrase at the amino acid level, viruses showed no statistically significant differences in growth kinetics compared with the reference HIVNL4−−3virus and only minor differences were observed in 3′ end-processing and disintegration activities. All integrase proteins demonstrated similar sensitivity to an integrase inhibitor l-chicoric acid.ConclusionsThese results demonstrate that integrase genes derived from HIV-infected individuals can differ from reference sequences but these mutations do not result in loss of function, including susceptibility to an integrase inhibitor; therefore, integrase remains an attractive target for antiviral drug design, as mutability appears to be restricted by function.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectivesTo determine how representative the genotype of HIV-1 circulating in plasma is of the genotype of the virus present in lymphoid tissue.MethodsPaired plasma and tonsillar tissue samples were prospectively obtained from patients with various levels of plasma HIV-1 RNA who were receiving combination antiretroviral therapy. HIV-1 reverse transcriptase and protease sequences were amplified from plasma and lymphoid tissue specimens by nested polymerase chain reaction and analyzed using an automated sequencing system. Results were compared with consensus HIV-1 sequences to determine whether drug-resistance mutations were present in the regions analyzed.ResultsHIV-1 protease sequences were compared in 11 plasma/tissue pairs obtained from eight patients; HIV reverse transcriptase sequences were compared in 12 plasma/tissue pairs obtained from nine patients. Sequence homology between plasma and tissue RNA, tissue RNA and DNA, and plasma and tissue DNA ranged from 97% to 100%. Few discrepancies were found when the percentage of mutant sequences at resistance codons was compared among paired samples. In most instances, tissue RNA or plasma contained a higher percentage of mutant sequences than did tissue DNA.ConclusionThe genotype of plasma HIV-1 is similar to the genotype of the virus in lymphoid tissue. Resistance studies using plasma samples should provide accurate information regarding the genotype of HIV-1 in lymphoid tissues.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveTo describe initial viral dissemination to peripheral tissues and infectious body fluids during human primary HIV infection.DesignObservational cohort study.MethodsBlood plasma, cerebrospinal fluid (CSF), seminal plasma, cervicovaginal lavage fluid and/or saliva were sampled from 17 individuals with primary HIV infection (range of time from symptoms onset to sampling, 8–70 days) and one individual with early infection (168 days). Subjects’ HIV-1 RNA levels in each fluid were compared with levels from antiretroviral-naive controls with established HIV infection. For study subjects, correlations were assessed between HIV-1 RNA levels and time from symptoms onset. Responses to antiretroviral therapy with didanosine + stavudine + nevirapine ± hydroxyurea were assessed in each compartment.ResultsHIV-1 RNA levels were highest closest to symptoms gnset in blood plasma (18 patients) and saliva (11 patients). CSF HIV-1 RNA levels (five patients) appeared lower closer to symptoms onset, although they were higher overall in primary versus established infection. Shedding into seminal plasma (eight patients) and cervicovaginal fluid (two patients) was established at levels observed in chrgnic infection within 3–5 weeks of symptoms onset. High-level seminal plasma shedding was associated with coinfection with other sexually transmitted pathogens. Virus replication was suppressed in all compartments by antiretroviral therapy.ConclusionsPeak level HIV replication is established in blood, oropharyngeal tissues and genital tract, but potentially not in CSF, by the time patients are commonly diagnosed with primary HIV infection. Antiretroviral therapy is unlikely to limit initial virus spread to most tissue compartments, but may control genital tract shedding and central nervous system expansiof in primary infection.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

BackgroundChanges 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.MethodThe 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).ResultsLipodystrophy 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).ConclusionThis 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.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Topical microbicides are products that are being developed to prevent HIV infection and other sexually transmitted diseases (STD) through topical application to the genital and rectal epithelial surfaces. This paper is an update of the clinical section of a general guidance for the development and evaluation of microbicidal products that was first published by the International Working Group on Microbicides (IWGM) in 1996. (The preclinical section of that document will be updated separately later.) All topical microbicides should be clinically evaluated in humans for safety and effectiveness. Safety studies are necessary to evaluate the potential for systemic absorption and toxicity as well as local toxic effects, such as irritation, ulceration, burning, and itching. Reported symptoms of burning and itching are relevant to future product use and acceptability. Irritation and ulceration of the vaginal, cervical, penile, or rectal epithelium have the potential to result in an increased transmission of HIV and other STD. Effectiveness studies to assess the prevention of HIV infection or STD, depending upon the product indication, are subsequently conducted. These trials need to be large enough to detect clinically meaningful levels of protection. For spermicidal microbicides, additional contraceptive effectiveness studies are also needed.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

BackgroundIn sub-Saharan Africa, malnutrition is a major complication of HIV disease. Measuring accurately the nutritional benefits of a therapeutic intervention could be an easy-to-monitor secondary outcome.MethodsAnthropometric data were analysed from patients participating in a placebo-controlled trial of co-trimoxazole prophylaxis in adults recruited at early stages of HIV-1 infection in Côte d'Ivoire (COTRIMO-CI ANRS 059 trial). Body mass index (BMI), arm muscle circumference (AMC) and percentage of fat mass (FM) were measured at baseline and quarterly during the follow up. Percentage of variation from the baseline value was compared between treatment groups and within the groups using Studentt-test.ResultsAn improvement of all anthropometric indicators was observed in the first 3 months of follow up in both treatment groups, significant in the co-trimoxazole group (P⩽ 0.0006) but not in the placebo group (P⩾ 0.06). In the co-trimoxazole group, this improvement was maintained for up to 24 months for BMI (P= 0.007), 21 months for AMC (P= 0.02) and only up to 12 months for FM (P= 0.04). The placebo group had a stable anthropometric status up to the end of the trial. Differences between treatment groups were significant for up to 15 months for BMI and AMC and 12 months for FM.ConclusionAs co-trimoxazole prophylaxis is now recommended in Africa as part of a minimum package of care for HIV-infected symptomatic subjects, the short-term improvement of these anthropometric indicators in adults who start co-trimoxazole prophylaxis should be considered as an effective clinical outcome.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveTo estimate parameters of concurrent sexual partnerships in five urban populations in sub-Saharan Africa and to assess their association with levels of HIV infection and other sexually transmitted infections (STI).MethodsData were obtained from a multicentre study of factors which determine the differences in rate of spread of HIV in five African cities. Consenting participants were interviewed on sexual behaviour and at four of the five sites also provided a blood and a urine sample for testing for HIV and other STI. Data on sexual behaviour included the number of partnerships in the 12 months preceding the interview as well as the dates of the start and end of each partnership. Summary indices of concurrent sexual partnerships – some of which were taken from the literature, while others were newly developed – were computed for each city and compared to HIV and STI prevalence rates.ResultsA total of 1819 adults aged 15–49 years were interviewed in Dakar (Senegal), 2116 in Cotonou (Benin), 2089 in Yaoundé (Cameroon), 1889 in Kisumu (Kenya) and 1730 in Ndola (Zambia). Prevalence rates of HIV infection were 3.4% for Cotonou, 5.9% for Yaoundé, 25.9% for Kisumu and 28.4% for Ndola, and around 1% for Dakar. The estimated fraction of sexual partnerships that were concurrent at the time of interview (indexk) was relatively high in Yaoundé (0.98), intermediate in Kisumu (0.44) and Cotonou (0.33) and low in Ndola (0.26) and in Dakar (0.18). An individual indicator of concurrency (iic) was developed which depends neither on the number of partners nor on the length of the partnerships and estimates the individual propensity to keep (positive values) or to dissolve (negative values) on-going partnership before engaging in another one. This measureiicdid not discriminate between cities with high HIV infection levels and cities with low HIV infection levels. In addition,iicdid not differ significantly between HIV-infected and uninfected people in the four cities where data on HIV status were collected.ConclusionWe could not find evidence that concurrent sexual partnerships were a major determinant of the rate of spread of HIV in five cities in sub-Saharan Africa. HIV epidemics are the result of many factors, behavioural as well as biological, of which concurrent sexual partnerships are only one.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID