Showing papers in "AIDS in 1999"

Sociodemographic and psychological variables influencing adherence to antiretroviral therapy.

Abstract: Objective To assess the degree of compliance with antiretroviral therapy in HIV-infected patients, and identify which sociodemographic and psychological factors influence it, in order to develop strategies to improve adherence. Design and setting Cross-sectional study in a reference HIV/AIDS institution located in Madrid, Spain. Patients and methods A total of 366 HIV-infected patients who were on treatment with antiretroviral drugs were invited to complete a questionnaire which recorded sociodemographic data and psychological variables in relation to compliance with the prescribed medication. Clinical information was extracted from the hospital records. The Beck Depression Inventory was used to assess depression, while adherence to treatment was evaluated using patient's self report and the pill count method. Results A good adherence to antiretroviral therapy (> 90% consumption of the prescribed pills) was recorded in 211 (57.6%) patients. A good concordance for assessing adherence was found using the patient's self-report and the pill count method in a sub-group of patients. Predictors of compliance in the univariate analysis were age, transmission category, level of studies, work situation, CD4 cell count level, depression and self-perceived social support. In the multivariate model, only age, transmission category, CD4 cell count level, depression, self-perceived social support, and an interaction between the last two variables predicted compliance to treatment; adherence to antiretroviral therapy was better among subjects aged 32-35 years [odds ratio (OR), 2.31; 95% confidence interval (CI), 1.21-4.40], in non-intravenous drug users (IVDUs) (OR, 2.05; 95% CI, 1.28-3.29), subjects with CD4 cell counts from 200-499 x 10(6) cells/l at enrolment (OR, 2.78; 95% CI, 1.40-5.51) and in subjects not depressed and with a self-perceived good social support (OR, 1.86; 95% CI, 0.98-3.53). Conclusions Sociodemographic and psychological factors influence the degree of adherence to antiretroviral therapy. Overall, IVDUs and younger individuals tend to have a poorer compliance, as well as subjects with depression and lack of self-perceived social support. An increased awareness of these factors by practitioners attending HIV-infected persons, recognizing and potentially treating some of them, should indirectly improve the effectiveness of antiretroviral therapy.

A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long-term nucleoside analogue therapy

Abstract: Objective: To compare body composition, body fat distribution and insulin secretion in patients taking nucleoside reverse transcriptase inhibitor (NRTI) therapy. Design and setting: Cross-sectional study in three French AIDS clinical centres. Patients: Forty-three HIV-infected patients on long-term NRTI therapy including stavudine (n = 27) or zidovudine (n = 16) and 15 therapy-naive HlV-infected patients (control group). Main outcome measures: Fat wasting was assessed by physical examination and body composition by bioelectrical impedance. Regional fat distribution was estimated using caliper measurements of skinfold thickness at four sites and evaluated by computed tomography at abdominal and mid-thigh level. Fasting glucose, insulin, C-peptide, triglyceride, cholesterol, free fatty acid, testosterone, follicle stimulating hormone, luteinizing hormone, cortisol levels, CD4 cell count and HIV viral load were determined. Daily total caloric and nutrient intake were evaluated. Results: The zidovudine group and the control group had similar body composition and regional fat distribution. Stavudine therapy was associated with a significantly lower percentage of body fat (12.9% versus 15.2% in the zidovudine group; P < 0.05), markedly decreased subcutaneous to visceral fat ratio (0.90 ± 0.63 versus 1.92 ± 1.34, P < 0.01) and higher mean intake of fat and cholesterol (P < 0.01). Fasting plasma glucose, insulin and C-peptide levels were similar among the three groups. Triglyceride levels were significantly higher in the stavudine group than in the controls (P < 0.05), but did not differ between the stavudine and the zidovudine group or between the zidovudine and the control group. Free fatty acids tended to be higher in the stavudine group but the difference did not reach statistical significance. Lipodystrophy was observed clinically in 17 (63%) patients taking stavudine, and in three (18.75%) patients taking zidovudine after a median time of 14 months. The relative risk of developing fat wasting was 1.95 in the stavudine group as compared with the zidovudine group (95% confidence interval, 1.18-3.22). Five out of 12 patients had a major or mild improvement in their lipodystrophy after stavudine was discontinued. Conclusion: Lipodystrophy may be related to long-term NRTI therapy, particularly that including stavudine.

The value of patient-reported adherence to antiretroviral therapy in predicting virologic and immunologic response. California Collaborative Treatment Group.

Abstract: Objective: To correlate self-reported antiretroviral adherence with virologic suppression. Design: Prospective observational study of adherence to therapy nested in a randomized comparative trial of frequent versus infrequent monitoring of plasma HIV RNA. Setting: Five university-affiliated HIV clinics. Patients: A group of 173 HIV-infected patients with a mean baseline CD4 count of 142 × 10 6 cells/l (range 3-515) of whom 164 and 119 completed adherence questionnaires at 2 and 6 months, respectively. Intervention: Individualized, unrestricted antiretroviral therapy. Measurements: Patients were classified into four groups by adherence to therapy in the previous 4 weeks (< 80%, 80-95%, 95-99%, 100%). Plasma HIV RNA levels and CD4 lymphocyte counts were measured bimonthly. Results: Recreational drug or alcohol use was associated with decreased adherence, whereas frequency of HIV RNA monitoring, demographic variables, (age, gender, education, and risk group) and stage of disease had no effect. Greater HIV suppression at 6 months was seen across four categories of increasing adherence (P = 0.009 for linear trend). Patients reporting < 80% adherence at 6 months had a 0.2 log 10 copies/ml increase in HIV RNA and a loss of 19 × 10 6 CD4 cells/l compared with a 1.1 log 10 copies/ml decrease in HIV RNA and an increase of 72 × 10 6 CD4 cells/l in those reporting 100% adherence (P = 0.02). Conclusion: Self-reported poor adherence (< 80%) and drug or alcohol use predicted non-response of HIV RNA at 6 months of antiretroviral therapy.

Impaired glucose tolerance, beta cell function and lipid metabolism in HIV patients under treatment with protease inhibitors.

Abstract: Objectives To evaluate metabolic abnormalities, beta-cell function, lipid profile and vascular risk factors in HIV patients on protease inhibitors (PI). Design Prospective cross-sectional study. Methods Thirty-eight HIV-1-infected patients receiving at least one PI were compared with 17 PI-naive HIV patients in an oral glucose tolerance test (OGTT). Serum glucose, insulin, proinsulin, and C-peptide were determined. The fasting lipid pattern was analysed using electrophoresis and the assessment of apolipoproteins including lipoprotein (a). Fibrinogen, homocysteine, and anticardiolipin antibodies were also assessed. Results Twenty-seven (71%) of the PI-treated group had detectable hyperlipidaemia. Isolated hypertriglyceridaemia was present in 12 patients (44%), two (7%) of them had type V and 10 (37%) subjects had type IV hyperlipidaemia (Frederickson classification). Type IIb hyperlipidaemia defined as an increase of both very-low-density lipoproteins (VLDL) and low-density lipoproteins (LDL) was found in 10 (36%) subjects, and five (18%) patients presented with isolated hypercholesterolaemia (type IIa). PI treatment was associated with significant higher fasting cholesterol, triglycerides, LDL and VLDL levels. Apolipoprotein B and E concentrations were significantly increased in patients receiving PI. Elevated concentrations of lipoprotein (a) (> 30 mg/dl) were detected in six (16%) of the hyperlipidaemic patients on PI. Eighteen (46%) patients on PI had impaired oral glucose tolerance and five (13%) had diabetes. Although four (24%) of the PI-naive patients were glucose intolerant, none had diabetes. Fasting concentrations and secretion response of insulin, proinsulin, and C-peptide to glucose ingestion was significantly increased in the PI-treated group suggesting a beta-cell dysfunction in addition to peripheral insulin resistance. Beta-cell abnormalities were associated with the abnormal lipid pattern and PI treatment. Conclusion Combination drug regimens including PI are accompanied by impaired glucose tolerance, hyperproinsulinaemia as an indicator for beta-cell dysfunction, and lipid abnormalities proved to be significant risk factors for coronary heart disease. Moreover, PI may have an impact on the processing of proinsulin to insulin.

Natural history of HIV infection in the era of combination antiretroviral therapy.

Abstract: Background: The use of protease inhibitor-containing (PI) combination antiretroviral therapy has led to a reduction in the incidence of opportunistic illness and mortality (events) in HIV infection. We wished to quantify the changing incidence of these events in our clinical practice and delineate the relationship between CD4, HIV-1 RNA, and development of events in patients receiving PI combination therapy. Methods: We assessed HIV-infected patients with CD4 counts ≤ 500 cells × 10 6 /l. We calculated the incidence of events from 1994 through 1998 and analyzed the association of temporal changes in event incidence and use of antiretroviral therapy. In patients on PI combination therapy, we determined the probability of achieving and maintaining an undetectable HIV-1 RNA response and determined the association of CD4, HIV-1 RNA, and developing an event. Results: The incidence of opportunistic illness declined from 23.7 events/100 person-years in 1994 to 14.0 events/100 person-years in 1998 (P < 0.001). Mortality declined from 20.2 deaths/100 person-years in 1994 to 8.4 deaths/ 100 person-years in 1998 (P < 0.001). Use of PI combination therapy was associated with a relative rate of opportunistic illness or death of 0.66 [95% confidence interval (CI), 0.51-0.85; P < 0.001]. The relative incidence of each of 16 opportunistic illnesses was approximately the same in 1998 as in 1994 except for lymphoma, cervical cancer and wasting syndrome which do not appeared to have declined in incidence. Approximately 60% of patients who received PI therapy achieved an undetectable HIV-1 RNA, and 65% of these patients maintained durable suppression of HIV-1 RNA. Achieving an undetectable HIV-1 RNA was associated with a decreased risk of an event, and was the variable most strongly associated with an increase in CD4 level. By multivariate analysis, the concurrent CD4 level was most strongly associated with developing an event. Conclusions: We observed a significant decline in the incidence of opportunistic illness and death from 1994 through 1998 associated with combination antiretroviral therapy. Patients who develop events while being treated with PI combination therapy were not likely to have achieved an undetectable HIV-1 RNA and are likely to have a low concurrent CD4 level.

Changes to AIDS dementia complex in the era of highly active antiretroviral therapy

Abstract: Objectives: To determine the protective efficacy of highly active antiretroviral therapy (HAART) against AIDS dementia complex (ADC) relative to other initial AIDS-defining illnesses (ADls), Australian AIDS notification data over recent years were examined. Methods: All initial ADls in Australia over the period 1992-1997 were included. Three initial ADI groups were established: ADC; other predominantly central nervous system (CNS) ADls (toxoplasmosis and cryptococcosis); and non-CNS ADls. For each ADI grouping, the proportion of total ADls, and median CD4 cell count in the pre-HAART era (1992-1995) were compared with the HAART era (1996 and 1997). Results: Initial ADls peaked in Australia in 1994 (n = 1049), with a gradual decline to 1996 (n = 722), and a marked decline in 1997 (n = 367). ADC constituted 4.4% of initial ADls over the period 1992-1995, but increased after the introduction of HAART to 6.0% in 1996 and 6.5% in 1997 (P = 0.02). In contrast, the proportion of other CNS ADls (1992-1995, 8.1%; 1996, 6.0%; 1997, 8.2%; P = 0.41) was stable over the period 1992-1997. The median CD4 cell count at ADC diagnosis increased from 70/mm 3 in 1992-1995 to 120/mm 3 in 1996 and 170/mm 3 in 1997 (P = 0.04). Although the median CD4 cell count also increased significantly over this period for both other CNS ADls (40-60/mm 3 P = 0.02), and non-CNS ADls (60-70/mm 3 ; P = 0.02), the increase was small. Conclusion: A proportional increase in ADC compared with other ADls and a marked increase in the median CD4 cell count at ADC diagnosis have occurred since the introduction of HAART in Australia. These changes suggest that HAART has a lesser impact on ADC than on other ADls, with the poor CNS penetration of many antiretroviral agents a possible explanation.

HIV RNA and CD4 cell count response to protease inhibitor therapy in an urban AIDS clinic: response to both initial and salvage therapy.

Abstract: Objective: To determine the HIV RNA and CD4 cell response to both initial and salvage therapy with protease inhibitor-based therapy, and to examine the relationship between the virological response and pre-therapy characteristics. Design: Observational cohort. Setting: University-based public hospital AIDS clinic. Patients: HIV-infected adults who received at least 16 continuous weeks' therapy with a potent protease inhibitor (indinavir, ritonavir or nelfinavir)-based regimen, and who have had at least 48 weeks of follow-up. Main outcome measures: Plasma HIV RNA and CD4 cell count response at week 48 of therapy for patients receiving their first protease inhibitor-containing regimen, and at week 24 of therapy with a salvage regimen. Results: Of the 337 patients analysed, 170 (50.2%) had a successful outcome (HIV RNA < 500 copies/ml after 48 weeks of treatment). Independent predictors of virological failure were higher baseline HIV RNA level, lower baseline CD4 cell count and failure to initiate at least one new nucleoside analog simultaneously at the time protease inhibitor therapy was initiated. The risk of failure increased incrementally across most HIV RNA and CD4 cell strata, with significant increases as the HIV RNA increased above 4.5 log 10 copies/ml and the CD4 cell count fell below 100 cells/mm 3 (P < 0.01). ). The CD4 cell count remained above baseline to week 48 in most patients, regardless of the HIV RNA response. Of the 99 patients who experienced virological failure and switched to a salvage regimen, only 22 (22%) achieved an undetectable HIV RNA level 24 weeks after initiating salvage therapy. Independent predictors of failure with salvage therapy included an HIV RNA greater than 4.0 log 10 RNA copies/m at the time of the switch and failure to use a non-nucleoside reverse transcriptase inhibitor (NNRTI) in the salvage regimen. Conclusion: Failure of potent protease inhibitor therapy to suppress HIV RNA levels below detectable levels is common in clinical practice, and can often be explained by their suboptimal use. CD4 T cell counts remain above baseline for at least one year in most patients experiencing virological failure. Successful salvage therapy, which was uncommon, was associated with a low plasma HIV RNA at the time of the switch and the use of a new class of antiretroviral agents (NNRTI) in the salvage regimen.

Anaemia is an independent predictive marker for clinical prognosis in HIV-infected patients from across Europe

Abstract: Objectives: To describe changes in haemoglobin over time and to determine the joint prognostic value of the current haemoglobin, CD4 lymphocyte count and viral load among patients from across Europe. Patients: The analysis included 6725 patients from EuroSIDA, an observational, prospective cohort of patients with HIV from across Europe. Methods: Normal haemoglobin was defined as haemoglobin greater than 14 g/dl for men and 12 g/dl for women; mild anaemia was 8-14 g/dl for men and 8-12 g/dl for women; severe anaemia was defined as less than 8 g/dl for both males and females. Linear regression techniques were used to estimate the annual change in haemoglobin; standard survival techniques were used to describe disease progression and risk of death. Results: At recruitment to the study, 40.4% had normal levels of haemoglobin, 58.2% had mild anaemia and 1.4% had severe anaemia. At 12 months after recruitment, the proportion of patients estimated to have died was 3.1% [95% confidence interval (CI) 2.3-3.9] for patients without anaemia, 15.9% for patients with mild anaemia (95% Cl 14.5-17.2) and 40.8% for patients with severe anaemia (95% CI 27.9-53.6; P < 0.0001). In a multivariate, time-updated Cox proportional hazards model, adjusted for demographic factors, AIDS status and each antiretroviral treatment as time-dependent covariates, a 1 g/dl decrease in the latest haemoglobin level increased the hazard of death by 57% [relative hazard (RH) 1.57; 95% Cl 1.41-1.75; P < 0.0001], a 50% drop in the most recent CD4 lymphocyte count increased the hazard by 51% (RH 1.51; 95% Cl 1.35-1.70; P < 0.0001) and a log increase in the latest viral load increased the hazard by 37% (RH 1.37; 95% Cl 1.15-1.63; P = 0.0005). Conclusions: Severe anaemia occurred infrequently among these patients but was associated with a much faster rate of disease progression. Among patients with similar CD4 lymphocyte counts and viral load, the latest value of haemoglobin was a strong independent prognostic marker for death.

Increased fitness of drug resistant HIV-1 protease as a result of acquisition of compensatory mutations during suboptimal therapy.

Abstract: Objective It is thought as a consequence of continuous replication, HIV-1 has acquired an optimal fitness state and that suboptimal antiretroviral therapy selects for drug resistant variants which show impaired fitness in the absence of the drug. In this paper we studied the evolution and fitness of viral populations appearing in a patient who received protease monotherapy. Methods Two factors contributing to fitness, drug resistance and protease catalytic activity, were studied at the enzymatic and virological level. Results The first drug resistant viral variants that were selected in vivo harboured one to three protease substitutions. These mutants showed reduced protease activity and consequently a reduction in viral replication capacity. During continued in vivo replication of these viruses in the presence of the drug, novel variants harbouring additional substitutions in the viral protease appeared. These variants did not display any further increase in drug resistance but demonstrated clearly increased protease activity. Consequently the replication capacity of these viruses was raised to a level at which they replicated better than the original wild-type virus. Conclusion This study indicates that the viral population in the patient does not have to represent the fittest possible variants, and thus antiretroviral therapy may drive the viral population first through a lower fitness level and then to a higher fitness level.

Fat distribution and metabolic changes in patients with HIV infection.

Abstract: Recent reports of localized areas of increased fat deposition and fat loss in HIV-infected patients, as well as changes in serum levels of metabolites and hormones, have led to the proposal that a lipodystrophy syndrome is occurring. Although the lipodystrophy syndrome is often attributed to the use of HIV protease inhibitor (PI) agents, there is no standard definition of the syndrome, attribution is often by self-report, and prevalence estimates vary widely. In addition, the association of lipodystrophy with use of PI, as well as the interrelationship of body composition changes with metabolic abnormalities, have been challenged. In this review we describe prevalence estimates derived from a review of the English language medical literature with regard to regional increases in fat (lipohypertrophy: 1-56%), regional loss of fat (lipoatrophy; 1-24%), and pooled 'lipodystrophy' syndromes (2-83%). The wide range of prevalence estimates may be due to differing definitions, methods (e.g. self-report versus objective measurements) and patient populations. The relationship of changes in body composition to use of PI is increasingly less clear, and analysis reveals multiple other potential contributing factors such as other classes of antiretroviral agents, duration of antiretroviral therapy, change in viral load, body weight, age, and gender. There are few data on the association of individual changes in fat redistribution with each other. Moreover, the association between fat distribution and metabolic changes such as hyperlipidemia and insulin resistance is also increasingly questioned; PI may play an independent role in metabolic changes. Future studies must examine each localized abnormality in fat distribution discretely, using objective measurements rather than subjective report. Discernment of contributing cofactors is critical and must include, among others, complete medication history, viral load, body weight, age and gender. Because some of the reported changes occur in non-HIV-infected individuals, it is important to calculate the excess prevalence above control populations. The association of individual changes with each other and with contributing factors must be analyzed first, before the definition of a syndrome or of multiple syndromes can be made.

Reversion of metabolic abnormalities after switching from Hiv-1 protease inhibitors to nevirapine

Abstract: Objectives: To assess the effects of switching from HIV-1 protease inhibitors (PI) to nevirapine on metabolic abnormalities in patients with fat redistribution and on CD4 T lymphocytes and plasma HIV-1 RNA. Design: Longitudinal data analysis of 23 consecutive patients treated with two nucleoside reverse transcriptase inhibitors and at least one PI who decided to stop PI despite sustained virological supression (< 200 copies/ml) because of psychological repercussions caused by body changes. PI were replaced by nevirapine in all patients. Methods: Physical examination [including measurements of body mass index (BMI) and waist: hip ratio (WHR)], fasting cholesterol, triglycerides, glucose, insulin, CD4 T lymphocytes and plasma HIV-1 RNA were performed at baseline and every 3 months. Results: Awareness of body changes occurred after a median of 12 months (range, 6-26 months) from the commencement of PI. Seventeen patients complained of increased abdominal girth (in 15 also of peripheral fat wasting) and six of peripheral fat wasting only. Hypertriglyceridemia (≥ 200 mg/dl) was present in 23 (100%), hypercholesterolemia (≥ 200 mg/dl) in 18 (78%), and impaired fasting glucose (≥ 110 mg/dl) in seven (30%) patients. Baseline CD4 T lymphocytes were 514 × 10 6 /l (range, 83-994 × 10 6 /l). HIV-1 RNA had been < 200 copies/ml a median of 9 months (range, 3-14 months) prior to withdrawal of PI. Median follow-up from the replacement of PI by nevirapine was 8 months (range, 7-11 months). Six months after PI withdrawal there was a significant improvement in cholesterol (decrease of 22%; P = 0.0005), triglycerides (decrease of 57%; P = 0.0001), glucose (decrease of 15%; P = 0.008), and fasting insulin resistance index (decrease of 45%; P = 0.0001). CD4 T-lymphocyte counts remained unchanged (401 × 10 6 /l; range, 57-941 × 10 6 /l; P = 0.13) and in only one patient did the viral load become detectable at a low count (546 copies/ml; P = 0.32). BMI did not vary (23.30 versus 23.56 kg/m 2 ; P = 0.73), but WHR decreased significantly from 0.91 to 0.85 (P = 0.048). Twenty-one patients (91%) subjectively reported a partial improvement in their body shape (particularly in peripheral fat wasting), although none admitted to have their body shaped as prior to body changes. Conclusions: Metabolic abnormalities associated with potent antiretroviral regimens including PI may revert at least partially, whereas the suppression achieved may be preserved at least at mid-term after replacing PI by nevirapine.

Astrocytes: HIV cellular reservoirs and important participants in neuropathogenesis

Abstract: IntroductionHIV can invade cells of the central nervous system (CNS) and cause progressive combined cognitive and motor impairment in infected individuals. The cellular basis and mechanisms underlying HIV-1 neuropathogenesis are complex and poorly understood. Astrocytes are the most abundant cell ty

Redistribution of body fat in HIV-infected women undergoing combined antiretroviral therapy

Abstract: Objectives: To investigate the prevalence, metabolic features and risk factors of a particular pattern of fat redistribution (FR), characterized by a progressive enlargement of breast and abdominal girth associated with a wasting of the lower limbs, observed in HIV-infected women treated with combined antiretroviral (ARV) therapy. Design: Cross-sectional study. Setting: Outpatients attending the Institute of Infectious Diseases, University of Milan, Milan, Italy. Patients and methods: HIV-infected women treated with two or more ARV drugs, observed between December 1997 and February 1998. FR was confirmed by means of a physical examination and dual-energy X-ray absorptiometry (DEXA). The metabolic and endocrinological measurements in patients with FR were compared with those in FR-free women. Results: FR was observed in 32 out of 306 women (10.5%). DEXA revealed more trunk fat (P < 0.01) and less leg fat (P < 0.001) in the patients with FR than in the matched controls. There were no significant differences in laboratory test results between the two groups. All of the FR patients were taking lamivudine-containin regimens; 20 of them were also taking a protease inhibitor (PI). The association of FR with lamivudine-including regimens was statistically significant (P = 0.017). Among the patients taking lamivudine, the risk associated with treatments including PI was 1.8 (95% CI 0.8-3.8, P = 0.12). A total duration of ARV therapy of more than 1000 days was associated with a greater risk of developing FR (OR 10.8; 95% Cl 1.4-80.5; P = 0.0207), Stepwise logistic regression analyses indicated that prolonged ARV therapy and a viral load of more than 10 000 copies per ml at the beginning of the last ARV regimen were the only variables that significantly and independently correlated with the risk of FR. Conclusions: The observed body modifications are caused by a redistribution of body fat without fat loss that is apparently not associated with hyperlipidemia, altered glucose metabolism or other endocrinological disorders. The development of FR in patients receiving only reverse transcriptase (RT) inhibitors suggests the presence of a PI-independent mechanism that deserves further investigation.

Rapid decline in detectability of HIV-1 drug resistance mutations after stopping therapy.

Abstract: Objective: To investigate the rate of decline of drug resistant viruses after stopping therapy. Design: Twenty-five patients receiving multiple combination therapies (mean five; range three to nine drugs) for more than 3 months were tested for HIV-1 resistance on therapy and off therapy. The sample off therapy was tested 6-175 day c after stopping therapy. Methods: Patients were tested for genotypic changes associated with drug resistance using an in-house automated DNA sequencing assay to detect resistance in the protease and reverse transcriptase genes. Results: All samples tested when patients were on therapy showed evidence of drug resistance (range 1-9 mutations). The patients were divided into three groups: < 2 weeks after stopping therapy, median 1.1 weeks In = 8, group A); 2 weeks-2 months, median 6.4 weeks In = 7, group B) and 2 months-6 months, median 12.9 weeks In = 10, group C). Of primary mutations (protease: 30N, 461/L, 82A, 90M; reverse transcriptase: 70R, 1841/V, 215 Y/F) detected on therapy 100% remained after stopping therapy in group A; 68% remained in group B and 15% remained in group C. For secondary mutations 98% remained in group A; 99% remained in group B and 57% in group C. Conclusions: This study showed a rapid decline in detectability of the majority of primary mutations within 13 weeks of stopping combination therapy. From this data, HIV-1 resistance testing to direct patients' therapy should only be carried out when on existing therapy, or < 2 weeks off therapy, if reliable decisions are to be made relating to future combinations.

Rates of HIV-1 transmission within marriage in rural Uganda in relation to the HIV sero-status of the partners.

Abstract: The objective was to assess the efficacy of transmission of HIV-1 within married couples in rural Uganda according to the sero- status of the partners. HIV incidence rates were estimated for 2200 adults in a population cohort followed for 7 years comparing male-to-female with female-to-male transmission and sero- discordant with concordant sero-negative couples. Each year adults (over 12 years of age) resident in the study area were linked to their spouses if also censused as resident. The HIV sero-status was determined annually. At baseline 7% of married adults were in sero-discordant marriages and in half of these the man was HIV-positive. Among those with HIV-positive spouses the age-adjusted HIV incidence in women was twice that of men (rate ratio (RR) = 2.2 95% confidence interval (CI) 0.9-5.4) whereas among those with HIV-negative spouses the incidence in women was less than half that of men (RR = 0.4 95% CI 0.2-0.8). The age- adjusted incidence among women with HIV-positive spouses was 105.8 times (95% CI 33.6-332.7) that of women with HIV-negative spouses the equivalent ratio for men being 11.6 (95% CI 5.8-23.4). Men are twice as likely as women to bring HIV infection into a marriage presumably through extra-marital sexual behavior. Within sero-discordant marriages women become infected twice as fast as men probably because of increased biological susceptibility. Married adults particularly women with HIV- positive spouses are at very high risk of HIV infection. Married couples in this population should be encouraged to attend for HIV counseling together so that sero-discordant couples can be identified and advised accordingly. (authors)

Reductions in risk behaviour provide the most consistent explanation for declining HIV-1 prevalence in Uganda.

Abstract: To monitor the HIV-1 epidemic in western Uganda and the possible impact of interventions age-specific trends in HIV-1 prevalence during 1991-1997 among antenatal clinic (ANC) attenders in Fort Portal where a comprehensive AIDS control program has been implemented since 1991 were analyzed and results compared with outputs from a mathematical model simulating the HIV-1 epidemic in the country. Scenarios with and without behavior change were modelled. Sentinel surveillance data were compared with data from a population-based HIV-1 serosurvey at the study site which was conducted in early 1995. Data from 3271 ANC attenders found greater education and single status to be risk factors for HIV-1 infection. A significant decrease of risk for women with secondary school education over time was observed while the risk for illiterate women remained high. Among the 1045 women aged 15-19 years education and marital status-adjusted HIV-1 prevalence declined steadily from 32.2% to 10.3% over the period. For the 1010 women aged 20-24 years prevalence increased until 1993 from 19.9% to 31.7% then declined thereafter to 21.7% in 1997. These declining trends of HIV-1 prevalence probably reflect a reduced HIV-1 incidence attributable to changes in behavior. No clear trends of HIV-1 prevalence were found in older women.

Isoniazid prophylaxis for tuberculosis in HIV infection: a meta-analysis of randomized controlled trials

Abstract: Infection with M tuberculosis is the most common bacterial infection in humans and HIV infection is the strongest risk factor for tuberculosis (TB) The World Health Organization estimates that more than 4 million people mostly in Africa are coinfected with both organisms Randomized controlled trials however have demonstrated that isoniazid (INH) prophylaxis may reduce the incidence of TB in HIV-negative populations at high risk of developing active disease The efficacy of INH in preventing TB in tuberculin skin test-positive and negative individuals with HIV infection was assessed through the meta-analysis of 7 randomized controlled trials from Mexico Haiti the US Zambia Uganda and Kenya Findings are based upon 2367 subjects treated with INH and 2162 in control and placebo groups The mean follow-up of trial participants varied between 04 and 32 years Pooling all 7 trials the risk ratio (RR) of INH versus placebo for TB was 058 and 094 for death In groups of tuberculin skin test-positive and -negative subjects the RR of TB was 040 and 084 respectively and the difference in the effectiveness of INH versus placebo between the groups was statistically significant Consistency of results was found across trials for all comparisons Prophylaxis with INH therefore reduces the risk of TB in HIV-infected individuals However the effect is limited to tuberculin skin test-positive persons

HIV-1-specific mucosal IgA in a cohort of HIV-1-resistant Kenyan sex workers.

Abstract: Most HIV-1 transmission is sexual; therefore immune responses in the genital mucosa may be important in mediating protection against HIV infection. This study examined HIV-1-specific mucosal immunoglobulin A (IgA) in a cohort of HIV-1-resistant Kenyan female sex workers. HIV-1-specific immune responses were compared in HIV-1-resistant and HIV-1-infected sex workers and in lower risk uninfected women. Cervical and vaginal samples from each group were tested for HIV-1-specific IgA and IgG by enzyme immunoassay. Systemic T-helper lymphocyte cell responses to HIV-1 envelope peptide epitopes were assayed using an interleukin 2 bioassay. HIV-1 risk-taking behaviors were assessed using standardized questionnaires. HIV-1-specific IgA was present in the genital tract of 16 out of 21 (76%) HIV-1-resistant sex workers 5 out of 19 (26%) infected women and 3 out of 28 (11%) lower-risk women (P < 0.0001). Among lower risk women the presence of HIV-1-specific IgA was associated with HIV-1 risk- taking behavior. Systemic T-helper lymphocyte responses to HIV-1 envelope peptides were present in 11 out of 20 (55%) HIV-1- resistant women 4 out of 18 (22%) infected women and 1 out of 25 (4%) lower-risk women (P < 0.001). T-helper lymphocyte responses did not correlate with the presence of titer of virus-specific mucosal IgA in any study group. HIV-1-specific IgA is present in the genital tract of most HIV-1-resistant Kenyan sex workers and of a minority of lower risk uninfected women where it is associated with risk-taking behavior. These data suggest a role for mucosal HIV-1-specific IgA responses in HIV-1 resistance independent of host cellular responses. (authors)

Dynamics of viral load rebound and immunological changes after stopping effective antiretroviral therapy.

Abstract: Background This study addresses the dynamic of viral load rebound and immune system changes in a cohort of eight consecutive HIV-1-infected patients in very early stages [all the patients were taking highly active antiretroviral therapy (HAART} and were recruited in the coordinating center from a larger study] who decided to discontinue HAART after 1 year of treatment and effective virologic response The safety of this procedure and the outcome with reintroduction of the same treatment was also investigated Methods Plasma, cerebrospinal fluid (CSF), and lymphatic tissue viral loads were measured at baseline; lymphocyte immunophenotyping and CD4 lymphocyte proliferative responses to mitogens and specific antigens were assessed The same antiretroviral therapy was reintroduced as soon as plasma viral load became detectable (above 200 copies/ml) Results At day 0, plasma viral load was below 20 copies/ml in all eight patients (and below 5 copies/ml in five of eight patients) A rebound in plasma viral load was detected in all patients from day 3 to day 31 with a mean doubling time of 201 (SE 029) days Three out of eight patients achieved a peak plasma viral load at least 05 log10 above baseline, pretreatment values Mutations associated with resistance to reverse transcriptase or protease inhibitors were not detected After 31 days off therapy, CD4 lymphocytes decreased [mean 45% (SE 4) to 37% (SE 3); P = 004], CD8+CD28+ lymphocytes decreased [mean 59% (SE 5) to 43% (SE 4); P = 003], and CD8+CD38+ lymphocytes increased [mean 55% (SE 3) to 66% (SE 4); P = 0009] Mean stimulation indices of lymphocytes treated with phytohemagglutinin (PHA) and CD3 decreased from day 0 to day 31 from 34% (SE 8) to 17% (SE 9) (P = 006) and from 24% (SE 8) to 5% (SE 2) (P = 002), respectively These changes were mainly contributed by the group of five patients with plasma viral load below 5 copies/ml at day 0 Viral load dropped below 20 copies/ml in all patients after 1 month of restarting the same antiretroviral regimen Conclusions Discontinuation of HAART after 1 year of successful treatment is followed by a rapid rebound of viral load; this rapidly returns to undetectable levels following reintroduction of the same treatment In patients with more effective control of virus replication (viremia below 5 copise/ml), discontinuation of treatment was associated with more severe impairment of immunologic parameters

The effect of Plasmodium falciparum malaria on HIV-1 RNA blood plasma concentration

Abstract: Objectives: This study was undertaken to determine the relative effect of malaria infection on HIV concentration in blood plasma, and prospectively to monitor viral concentrations after antimalarial therapy. Design: A prospective, double cohort study was designed to compare the blood HIV-1 RNA concentrations of HIV-positive individuals with and without acute malaria illness. Subjects were followed for 4 weeks after successful malaria therapy, or for 4 weeks from enrollment (controls). Methods: Malawian adults with symptomatic Plasmodium falciparum parasitemia (malaria group) and asymptomatic, aparasitemic blood donors (control group) were tested for HIV-1 antibodies to identify appropriate study groups. The malaria group received antimalarial chemotherapy only and were followed with sequential blood films. In both groups, blood plasma HIV-1 RNA viral concentrations were determined at enrollment and again at 1, 2 and 4 weeks. Results: Forty-seven malaria patients and 42 blood donors were enrolled. At enrollment blood plasma HIV-1 RNA concentrations were approximately sevenfold higher in patients with malaria than in blood donors (medians 15.1 × 10 4 and 2.24 × 10 4 copies/ml, respectively, P = 0.0001). No significant changes in median HIV-1 concentrations occurred in the 21 blood donors followed to week 4 (P = 0.68). In the 27 subjects successfully treated for malaria who were followed to week 4, a reduction in plasma HIV-1 RNA was observed from a median of 19.1 × 10 4 RNA copies/ml at enrollment, to 12.0 × 10 4 copies/ml at week 4, (P = 0.02). Plasma HIV-1 concentrations remained higher in malaria patients than controls (median 12.0 × 10 4 compared with 4.17 × 10 4 copies/ml, P = 0.086). Conclusions: HIV-1 blood viral burden is higher in patients with P. falciparum malaria than in controls and this viral burden can, in some patients, be partly reduced with antimalarial therapy.

Rate of HIV-1 RNA rebound upon stopping antiretroviral therapy.

Abstract: Objective To determine the rate of plasma HIV-1 RNA rebound in patients stopping highly active antiretroviral therapy (HAART) after achieving undetectable viral load. Design Sequential plasma HIV RNA levels were measured in six patients during the 21 days following withdrawal from HAART. Methods Plasma samples were obtained from six patients who chose to withdraw from HAART because of lipodystrophy, narcotic overdose, insomnia and/or high blood pressure. Longitudinal plasma viral load was determined in triplicate upon stopping therapy. Results All patients had plasma viral loads below 50 HIV RNA copies/ml at the time of stopping therapy and had had levels below 500 copies/ml for a median of 390 days (range 39-542 days). Plasma HIV rebound upon stopping therapy was rapid (median increase 0.2 log/day; range 0.15-0.42 log/day) and initially appeared to follow first-order kinetics. Plasma HIV RNA levels returned to greater than 500 copies/ml within 6 to 15 days (median 10 days) and approached or exceeded pre-therapy levels in all patients within 21 days of stopping therapy. Extrapolating backwards to the time at which individuals stopped therapy suggested that patients had tens of thousands of total body plasma HIV RNA copies despite having 'undetectable' plasma HIV RNA. Conclusions HIV RNA in plasma rebounds within days of stopping antiretroviral therapy. A considerable burden of total body plasma HIV RNA likely remains even during effective HAART therapy.

Gay men report high rates of unprotected anal sex with partners of unknown or discordant HIV status.

Abstract: Objective To examine patterns and factors that correlate with unprotected anal intercourse (UAI) practices among San Francisco gay men, including UAI with partners of unknown or different HIV antibody status. Design A longitudinal cohort recruited for the San Francisco Young Men's Health Study in 1992; re-assessed annually. Participants and methods A sample of 510 unmarried gay men who were 18 to 29 years at baseline were originally recruited as part of a larger population and referral-based sample. Subjects participated in four consecutive waves of data collection. Results The prevalence of reported unprotected anal intercourse (UAI) increased from 37% to 50% between 1993-1994 and 1996-1997. Almost half of all men who reported UAI in 1996-1997 indicated that it occurred with a partner of unknown or discordant HIV antibody status. This high-risk practice correlated with greater numbers of male sex partners, use of nitrite inhalants, sex in commercial sex environments, perceived difficulty controlling sexual risk-taking, and negative emotional reactions following UAI. Conclusions These data on increasing rates of sexual risk-taking further confirm trends in sexual behavior previously suggested by rising rates of rectal gonorrhea in this population. Additional and sustained prevention efforts are urgently needed in light of the very high background rates of HIV infection found among gay men in San Francisco.

Subcutaneous adipocyte apoptosis in HIV-1 protease inhibitor-associated lipodystrophy.

Abstract: Background: Inhibitors of HIV-1 protease produce a rapid decrease in plasma HIV-1 RNA, with concomitant immune reconstitution. However, severe metabolic side effects together with a previously unseen form of lipodystrophy have been associated with long-term use of protease-inhibitor therapy. The pathogenic mechanisms underlying HIV-1 protease inhibitor-associated lipodystrophy are still largely unknown. Methods: Fourteen HIV-infected patients with HIV-1 protease inhibitor-associated lipodystrophy had a biopsy of subcutaneous fat performed in the antero-lateral aspect of the right leg. The samples were submitted for standard pathologic study together with a careful search for adipocyte apoptosis. Apoptosis was assessed by the terminal deoxynucleotidyl transferase dUTP-digoxigenin nick end labelling (TUNEL) method, using the ApopTag kit (Oncor, Gaithersburg, Maryland, USA). The procedure was performed between three and five times for each sample. Appropriate positive and negative controls were used. Controls which were subcutaneous fat biopsies from patients with untreated melanoma were also examined for the presence of apoptosis. Results: Fourteen HIV-infected patients with a mean exposure to HIV-1 protease inhibitors of 12.6 ± 3.7 months (range: 6-21 months), developed the characteristic features of HIV-1 protease inhibitor-associated lipodystrophy. All but one patient had an abnormal waist : hip ratio, and they all exhibited an abnormal serum lipid profile. Pathologically, subcutaneous fat atrophy was a constant feature, along with focal lipogranuloma formation and vascular proliferation. One of the eleven assessable biopsy samples was negative for the presence of apoptosis, six showed focally positive apoptotic cells, and the remaining four biopsies demonstrated moderate positivity. Apoptotic changes were also detected in endothelial cells. Apoptotic changes were more pronounced in patients with higher increases in CD4 and CD8 counts, and in those with a greater decay in plasma viral load. Conclusions: Subcutaneous adipocyte apoptosis occurs in lipoatrophic areas of patients with HIV-1 protease inhibitor-associated lipodystrophy.

Randomized Trial Testing the Effect of Vitamin A Supplementation on Pregnancy Outcomes and Early Mother-to-Child HIV-1 Transmission in Durban, South Africa

Abstract: Poor vitamin A status has been associated with a higher risk for mother-to-child transmission of HIV-1 and there is contradictory evidence on the impact of vitamin A on perinatal outcome. The authors therefore assessed the effect of vitamin A supplementation to mothers on birth outcome and mother-to-child transmission of HIV-1. In Durban South Africa 728 pregnant HIV-infected women received either vitamin A (368) or placebo (360) in a randomized double-blind trial. The vitamin A treatment consisted of a daily dose of 5000 IU retinyl palmitate and 30 mg beta-carotene during the 3rd trimester of pregnancy and 200000 IU retinyl palmitate at delivery. HIV infection results were available on 632 children who were included in the Kaplan-Meier transmission analysis. Results are reported on mother-to-child transmission rates up to 3 months of age. There was no difference in the risk of HIV infection by 3 months of age between the vitamin A [20.3%; 95% confidence interval (CI) 15.7-24.9] and placebo groups (22.3%; 95% CI 17.5-27.1) nor were there differences in fetal or infant mortality rates between the two groups. Women receiving vitamin A supplement were however less likely to have a preterm delivery (11.4% in the vitamin A and 17.4% in the placebo group; P = 0.03) and among the 80 preterm deliveries those assigned to the vitamin A group were less likely to be infected (17.9% 95% CI 3.5-32.2) than those assigned to the placebo group (33.8%; 95% CI 19.8- 47.8). Vitamin A supplementation a low-cost intervention does not appear to be effective in reducing overall mother-to-child transmission of HIV; however its potential for reducing the incidence of preterm births and the risk of mother-to-child transmission of HIV in these infants needs further investigation. (authors)

A phase I / II study of the safety and pharmacokinetics of nevirapine in HIV-1-infected pregnant Ugandan women and their neonates (HIVNET 006).

Abstract: The transmission of HIV-1 infection from an infected mother to her infant is estimated to be 15-40% with more than half of transmission probably occurring late in pregnancy or during labor and delivery. Nevirapine a non-nucleoside reverse transcriptase inhibitor is an excellent candidate for a single-dose antiretroviral intervention administered during labor. Findings are presented from a study assessing the safety pharmacokinetics tolerance antiretroviral activity and infant HIV infection status following the administration of 1 dose of nevirapine to HIV-1-infected pregnant women during labor and their newborns during the first week of life. 200 mg of nevirapine were given as a single dose during labor to 21 HIV-1-infected pregnant women in Kampala Uganda. 8 of their infants did not receive the drug while 13 infants received 1 dose of nevirapine at 2 mg/kg at 72 hours of age. Nevirapine was well tolerated by both the women and infants with no serious adverse events related to the drug observed. Median nevirapine concentration in breast milk 1 week after delivery was 103 ng/ml. Plasma nevirapine concentrations remained above 100 ng/ml in all infants from both cohorts tested at age 7 days. Maternal HIV-1 RNA levels decreased by a median of 1.3 logs at 1 week postpartum and returned to baseline by 6 weeks postpartum. Detectable plasma HIV-1 RNA was observed in 1 of 22 (4.5%) infants at birth 3/21 (14%) at 6 weeks and 4/21 (19%) at 6 months of age. This regimen has promise as a prophylaxis against intrapartum and early breast milk HIV transmission in a breast-feeding population.

Immuno-activation with anti-CD3 and recombinant human IL-2 in HIV-1-infected patients on potent antiretroviral therapy

Abstract: Background A stable reservoir of latently infected, resting CD4 T cells has been demonstrated in HIV-1-infected patients despite prolonged antiretroviral treatment This is a major barrier for the eradication of HIV by antiretroviral agents alone Activation of these cells in the presence of antiretroviral therapy might be a strategy to increase the turnover rate of this reservoir Methods Three HIV-1-positive patients on potent antiretroviral therapy, in whom plasma viremia had been suppressed to below 5 copies/ml for at least 26 weeks, were treated with a combination of OKT3 (days 1-5) and recombinant human IL-2 (days 2 6) Results The side-effects were fever, headache, nausea, diarrhea, and in one of the patients transient renal failure and seizures The regimen resulted in profound T cell activation In one patient plasma HIV-1 RNA transiently increased with a peak at 1500 copies/ml In the other two patients plasma HIV-1 RNA levels remained below the detection limit, but HIV-1 RNA levels in the lymph nodes increased two- to threefold All patients developed antibodies against OKT3 Conclusion OKT3/IL-2 resulted in T cell activation and proliferation, and could stimulate HIV replication in patients having achieved prolonged suppression of plasma viremia OKT3/IL-2 therapy was toxic and rapidly induced antibodies against OKT3

A recombinant vaccinia virus based ELISPOT assay detects high frequencies of Pol-specific CD8 T cells in HIV-1-positive individuals

Abstract: OBJECTIVES HIV-1-specific CD8 T cells are considered to be critical in anti-HIV responses. It is important to quantify these cells and to determine their antigenic targets. Here quantification of interferon (IFN)-gamma secreting, virus-specific cells was achieved with an enzyme linked immuno spot (ELISPOT) assay. METHODS Peripheral blood mononuclear cells (PBMC) were infected with recombinant vaccinia vectors expressing HIV-1 genes (gag, pol, env or nef) and added to wells precoated with anti-IFN-gamma monoclonal antibodies. Spot forming cells (SFC), i.e. antigen-specific T cells were detected 24 h later by the addition of biotinylated anti-IFN-gamma monoclonal antibodies, followed by avidin-bound biotinylated horseradish peroxidase. RESULTS In a cohort of 19 patients, of whom 15 were on highly active antiretroviral therapy, 18 had primed T cells directed against one or more HIV-1 antigens (P 90% loss of antigen-specific SFC when vaccinia virus was used as a vector. The number of CD8 SFC exceeded the number of memory cells detected in limiting dilution assays by > 1 log10, whereas a correlation was found between the frequency of effector cells detected by both ELISPOT and MHC class I peptide tetramer assays. CONCLUSIONS Vaccinia virus vectors used in ELISPOT assays are useful for determining the frequency and specificity of CD8 T cells for individual HIV-1 gene products. The dominance of cytolytic T lymphocytes (CTL) recognizing pol proteins suggests that this antigen should be considered in vaccine strategies.

Attaining higher goals in HIV treatment: the central importance of adherence.

Abstract: In recent years, advances in HIV therapeutics have changed the nature of HIV/AIDS disease, so that it has now assumed some of the characteristics of a 'chronic' disease. Several factors have, however, qualified these advances. Social, economic, and clinical variables have confounded universal therapeutic success. Access to the highly active antiretroviral therapy is limited among marginalized populations, such as the homeless, or absent in many nations that have poor resources. In addition, study populations are often not fully representative of those actually cared for in clinical practice, who may respond differently to the study medications. Moreover, physiologic differences between patients may alter drug plasma levels, resulting in varying efficacy levels in different patients. Finally, and crucial among determinants of effective therapy, is a patient's level of adherence to the antiretroviral regimen. The magnitude of 'error-prone' viral replication makes resistance to antiretroviral agents invariable. In the presence of partially suppressive therapy, viral replication will select for viral variants with resistance mutations. Therefore, potent and continuous suppressive therapy for the duration of viral replicative capability is necessary for therapy to be effective. Factors that have an impact on adherence include characteristics of the treatment regimen, of patients and clinicians, and of the clinical setting. Successful adherence to therapeutic regimens is the responsibility of clinicians as well as patients. Many patient- and clinician-focused strategies and interventions that can improve adherence exist. The simplification of current antiviral regimens, without the loss of potency, is essential to achieving the goal of complete adherence. Maximizing the long-term benefit of highly active antiretroviral therapy requires knowledge of the technical and biologic aspects of HIV therapeutics, but necessitates an understanding of the behavioral aspects of therapeutics as well.

Sexual transmission of HIV: infectiousness and prevention.

Abstract: HIV can be transmitted through contaminated blood and blood products; from a mother to her offspring during pregnancy childbirth or breast feeding; or through sexual contact. Sexual transmission remains by far the predominant mode of transmission. Vertical and blood borne transmission of HIV are highly predictable and very efficient modes. The recipient of a unit of contaminated blood nearly always becomes infected whereas only about 0.3% of people pierced with large bore needles seroconvert. This difference in efficiency most probably reflects the dissimilar concentrations of viruses inoculated. Vertical transmission leads to infection in about 25% of newborns. Sexual transmission of HIV however appears to be considerably less efficient and highly variable. To develop effective prevention strategies a better understanding of the factors affecting transmission of HIV is required. (excerpt)