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Introduction
We report on the adherence experience of a group of people living with HIV on ART over six years in Uganda.Methods
Between 2005 and 2009, we followed up 41 participants who were also part of a clinical trial comparing home and facility based delivery of ART in Jinja, eastern Uganda. We conducted qualitative in-depth interviews at enrolment, 3, 6, 18 and 30 months to capture experiences with adherence over time. In 2011 we returned to these participants to find out how they were fairing with long term adherence. We managed to retrace 24 participants and interviewed them about their experience. We thematically analysed the data and compared findings over time.Results
Initially there were few barriers to adherence and many followed the adherence guidance closely. By year six, relaxation of these rules was noticeable although self-reported adherence continued to be high. Alcohol consumption was more common than before. Some relatives of the participants who had died claimed that some deaths were a result of alcohol. While participants reported that ART had allowed them to reclaim independence and return to work the changes in work and social routines created new challenges for adherence. Side effects like lipodystrophy were not only causing some stigma but for some tested their faith in the drugs. Many participants reported resumption of sexual lives but apart from those who selected same status partners, disclosure to new partners was minimal.Conclusion
Good adherence practice to ART wanes over the long-term, and people who may have disclosed at initiation find it difficult to do so to new partners once they are healthy. Further adherence interventions and support with disclosure over the course of therapy may need to be considered. (Words: 283) 相似文献3.
Summer L. Day Katherine Odem-Davis Kishorchandra N. Mandaliya Keith R. Jerome Linda Cook Linnet N. Masese John Scott H. Nina Kim Susan M. Graham R. Scott McClelland 《PloS one》2013,8(3)
Background
Sub-Saharan Africa carries a high burden of co-infection with HIV-1 and hepatitis B virus (HBV). In this region, individuals with HIV-1/HBV co-infection on antiretroviral therapy (ART) frequently receive lamivudine as the only agent active against HBV, raising concerns for development of HBV resistance to lamivudine. We aimed to determine the prevalence, clinical, and virologic outcomes of chronic HBV infection, including HBV resistance to lamivudine, in a cohort of HIV-1 seropositive Kenyan women on long-term ART.Methods
In this prospective cohort study, HIV-1 seropositive women initiated three-drug ART regimens that included lamivudine as the single drug active against HBV. Archived samples were tested for HBsAg, with further testing to determine HBeAg seroprevalence, HBV DNA suppression, and lamivudine resistance. We estimated the prevalence of chronic HBV and examined associations between HBV co-infection and clinical and virologic outcomes with chi-square tests, logistic regression, Kaplan-Meier and Cox regression.Results
In a cohort of 159 women followed for a median of 3.4 years (interquartile range 1.4–4.5), 11 (6.9%; 95% CI 3.1–10.7) had chronic HBV infection. Of these, 9 (82%) achieved undetectable plasma HBV DNA levels. One woman developed lamivudine resistance, for an incidence of 3 per 100 person-years. The HBV co-infected women were at greater risk for abnormal ALT elevations compared to HIV-1 mono-infected women (HR 2.37; 95% CI 1.1–5.3). There were no differences between HBV-infected and uninfected women in mortality, CD4 count, or HIV-1 RNA suppression.Conclusion
The prevalence of chronic HBV in this cohort was similar to recent studies from other African populations. Given our long-term follow-up, lamivudine resistance was lower than expected for HIV-1/HBV co-infected patients. Improved screening for HBV and extended follow-up of HIV-1/HBV co-infected individuals are needed to better understand the impact of different ART regimens on clinical outcomes in this population. 相似文献4.
Sheri D. Weiser David M. Tuller Edward A. Frongillo Jude Senkungu Nozmu Mukiibi David R. Bangsberg 《PloS one》2010,5(4)
Background
Food insecurity is emerging as an important barrier to antiretroviral (ARV) adherence in sub-Saharan Africa and elsewhere, but little is known about the mechanisms through which food insecurity leads to ARV non-adherence and treatment interruptions.Methodology
We conducted in-depth, open-ended interviews with 47 individuals (30 women, 17 men) living with HIV/AIDS recruited from AIDS treatment programs in Mbarara and Kampala, Uganda to understand how food insecurity interferes with ARV therapy regimens. Interviews were transcribed, coded for key themes, and analyzed using grounded theory.Findings
Food insecurity was common and an important barrier to accessing medical care and ARV adherence. Five mechanisms emerged for how food insecurity can contribute to ARV non-adherence and treatment interruptions or to postponing ARV initiation: 1) ARVs increased appetite and led to intolerable hunger in the absence of food; 2) Side effects of ARVs were exacerbated in the absence of food; 3) Participants believed they should skip doses or not start on ARVs at all if they could not afford the added nutritional burden; 4) Competing demands between costs of food and medical expenses led people either to default from treatment, or to give up food and wages to get medications; 5) While working for food for long days in the fields, participants sometimes forgot medication doses. Despite these obstacles, many participants still reported high ARV adherence and exceptional motivation to continue therapy.Conclusions
While reports from sub-Saharan Africa show excellent adherence to ARVs, concerns remain that these successes are not sustainable in the presence of widespread poverty and food insecurity. We provide further evidence on how food insecurity can compromise sustained ARV therapy in a resource-limited setting. Addressing food insecurity as part of emerging ARV treatment programs is critical for their long-term success. 相似文献5.
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Deidra D. Parrish Meridith Blevins Samuel E. Stinnette Peter F. Rebeiro Bryan E. Shepherd Timothy R. Sterling Catherine C. McGowan C. William Wester 《PloS one》2012,7(12)
Introduction
Mortality rates within the first year of combination antiretroviral therapy (cART) initiation are several-fold higher in resource-limited countries than in resource-replete settings. However studies in western countries examining virologic, immunologic and clinical responses after cART initiation in indigenous versus non-indigenous populations have shown mixed results. This study aimed to determine whether there is a difference in these outcomes in a United States setting between foreign-born and US-born patients.Methods
This retrospective observational cohort study of HIV-1 infected adults in one urban clinic in the United States compared virologic suppression, immune recovery and rates of AIDS defining events (ADEs) within the first year of cART using linear mixed effect models, log rank tests and Cox proportional hazard models. Data were analyzed for 94 foreign-born and 1242 US-born patients.Results
Foreign-born patients were younger (31.7 years versus 38.5 years), more often female (38.3% versus 27.1%), less often injection drug users (3.2% versus 9.5%) or men who have sex with men (19.0% versus 54.5%), and had higher loss to follow-up rates (14.9% versus 6.2%). No significant differences were detected between the groups in suppression of plasma HIV-1 RNA, CD4+ cell recovery or development of ADEs.Conclusions
During the first year on cART, virologic suppression, immune recovery and development of ADEs were comparable between foreign-born and US-born patients in care in a US clinic. Differential rates of loss to follow-up warrant further investigation in the foreign-born population. 相似文献7.
Joseph Kagaayi Ronald H. Gray Christopher Whalen Pingfu Fu Duncan Neuhauser Janet W. McGrath Nelson K. Sewankambo David Serwadda Godfrey Kigozi Fred Nalugoda Steven J. Reynolds Maria J. Wawer Mendel E. Singer 《PloS one》2014,9(4)
Introduction
Targeting most-at-risk individuals with HIV preventive interventions is cost-effective. We developed gender-specific indices to measure risk of HIV among sexually active individuals in Rakai, Uganda.Methods
We used multivariable Cox proportional hazards models to estimate time-to-HIV infection associated with candidate predictors. Reduced models were determined using backward selection procedures with Akaike''s information criterion (AIC) as the stopping rule. Model discrimination was determined using Harrell''s concordance index (c index). Model calibration was determined graphically. Nomograms were used to present the final prediction models.Results
We used samples of 7,497 women and 5,783 men. 342 new infections occurred among females (incidence 1.11/100 person years,) and 225 among the males (incidence 1.00/100 person years). The final model for men included age, education, circumcision status, number of sexual partners, genital ulcer disease symptoms, alcohol use before sex, partner in high risk employment, community type, being unaware of a partner''s HIV status and community HIV prevalence. The Model''s optimism-corrected c index was 69.1 percent (95% CI = 0.66, 0.73). The final women''s model included age, marital status, education, number of sex partners, new sex partner, alcohol consumption by self or partner before sex, concurrent sexual partners, being employed in a high-risk occupation, having genital ulcer disease symptoms, community HIV prevalence, and perceiving oneself or partner to be exposed to HIV. The models optimism-corrected c index was 0.67 (95% CI = 0.64, 0.70). Both models were well calibrated.Conclusion
These indices were discriminative and well calibrated. This provides proof-of-concept that population-based HIV risk indices can be developed. Further research to validate these indices for other populations is needed. 相似文献8.
Hiroyu Hatano Steven A. Yukl April L. Ferre Erin H. Graf Ma Somsouk Elizabeth Sinclair Mohamed Abdel-Mohsen Teri Liegler Kara Harvill Rebecca Hoh Sarah Palmer Peter Bacchetti Peter W. Hunt Jeffrey N. Martin Joseph M. McCune Russell P. Tracy Michael P. Busch Una O'Doherty Barbara L. Shacklett Joseph K. Wong Steven G. Deeks 《PLoS pathogens》2013,9(10)
The study of HIV-infected “controllers” who are able to maintain low levels of plasma HIV RNA in the absence of antiretroviral therapy (ART) may provide insights for HIV cure and vaccine strategies. Despite maintaining very low levels of plasma viremia, controllers have elevated immune activation and accelerated atherosclerosis. However, the degree to which low-level replication contributes to these phenomena is not known. Sixteen asymptomatic controllers were prospectively treated with ART for 24 weeks. Controllers had a statistically significant decrease in ultrasensitive plasma and rectal HIV RNA levels with ART. Markers of T cell activation/dysfunction in blood and gut mucosa also decreased substantially with ART. Similar reductions were observed in the subset of “elite” controllers with pre-ART plasma HIV RNA levels below conventional assays (<40 copies/mL). These data confirm that HIV replication persists in controllers and contributes to a chronic inflammatory state. ART should be considered for these individuals (ClinicalTrials.gov ). NCT01025427相似文献
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Wolfgang St?hr Sarah Fidler Myra McClure Jonathan Weber David Cooper Gita Ramjee Pontiano Kaleebu Giuseppe Tambussi Mauro Schechter Abdel Babiker Rodney E. Phillips Kholoud Porter John Frater 《PloS one》2013,8(10)
Objective
A minority of HIV-1 positive individuals treated with antiretroviral therapy (ART) in primary HIV-1 infection (PHI) maintain viral suppression on stopping. Whether this is related to ART duration has not been explored.Design
And Methods: Using SPARTAC trial data from individuals recruited within 6 months of seroconversion, we present an observational analysis investigating whether duration of ART was associated with post-treatment viraemic control. Kaplan-Meier estimates, logistic regression and Cox models were used.Results
165 participants reached plasma viral loads (VL) <400 copies/ml at the time of stopping therapy (ART stop). After ART stop, 159 experienced confirmed VL ≥400 copies/ml during median (IQR) follow-up of 167 (108,199) weeks.Most participants experienced VL rebound within 12 weeks from ART stop, however, there was a suggestion of a higher probability of remaining <400 copies/ml for those on ART >12 weeks compared to ≤12 weeks (p=0.061). Cumulative probabilities of remaining <400 copies/ml at 12, 52 and 104 weeks after ART stop were 21% (95%CI=13,30), 4% (1,9), and 4% (1,9) for ≤12 weeks ART, and 32% (22,42), 14% (7,22), and 5% (2,11) for >12 weeks.In multivariable regression, ART for >12 weeks was independently associated with a lower probability of being ≥400 copies/ml within 12 weeks of ART stop (OR=0.11 (95%CI=0.03,0.34), p<0.001)). In Cox models of time to VL ≥400 after 12 weeks, we only found an association with female sex (OR=0.2, p=0.001).Conclusion
Longer ART duration in PHI was associated with a higher probability of viral control after ART stop.Trial Registration
Controlled-Trials.com 76742797 http://www.controlled-trials.com/ISRCTN76742797. 相似文献11.
Brandon J. Auerbach Steven J. Reynolds Mohammed Lamorde Concepta Merry Collins Kukunda-Byobona Ponsiano Ocama Aggrey S. Semeere Anthony Ndyanabo Iga Boaz Valerian Kiggundu Fred Nalugoda Ron H. Gray Maria J. Wawer David L. Thomas Gregory D. Kirk Thomas C. Quinn Lara Stabinski Rakai Health Sciences Program 《PloS one》2012,7(11)
Background
Traditional herbal medicines are commonly used in sub-Saharan Africa and some herbs are known to be hepatotoxic. However little is known about the effect of herbal medicines on liver disease in sub-Saharan Africa.Methods
500 HIV-infected participants in a rural HIV care program in Rakai, Uganda, were frequency matched to 500 HIV-uninfected participants. Participants were asked about traditional herbal medicine use and assessed for other potential risk factors for liver disease. All participants underwent transient elastography (FibroScan®) to quantify liver fibrosis. The association between herb use and significant liver fibrosis was measured with adjusted prevalence risk ratios (adjPRR) and 95% confidence intervals (CI) using modified Poisson multivariable logistic regression.Results
19 unique herbs from 13 plant families were used by 42/1000 of all participants, including 9/500 HIV-infected participants. The three most-used plant families were Asteraceae, Fabaceae, and Lamiaceae. Among all participants, use of any herb (adjPRR = 2.2, 95% CI 1.3–3.5, p = 0.002), herbs from the Asteraceae family (adjPRR = 5.0, 95% CI 2.9–8.7, p<0.001), and herbs from the Lamiaceae family (adjPRR = 3.4, 95% CI 1.2–9.2, p = 0.017) were associated with significant liver fibrosis. Among HIV infected participants, use of any herb (adjPRR = 2.3, 95% CI 1.0–5.0, p = 0.044) and use of herbs from the Asteraceae family (adjPRR = 5.0, 95% CI 1.7–14.7, p = 0.004) were associated with increased liver fibrosis.Conclusions
Traditional herbal medicine use was independently associated with a substantial increase in significant liver fibrosis in both HIV-infected and HIV-uninfected study participants. Pharmacokinetic and prospective clinical studies are needed to inform herb safety recommendations in sub-Saharan Africa. Counseling about herb use should be part of routine health counseling and counseling of HIV-infected persons in Uganda. 相似文献12.
Background
The development of tipranavir and darunavir, second generation non-peptidic HIV protease inhibitors, with marked improved resistance profiles, has opened a new perspective on the treatment of antiretroviral therapy (ART) experienced HIV patients with poor viral load control. The aim of this study was to determine the virologic response in ART experienced patients to tipranavir-ritonavir and darunavir-ritonavir based regimens.Methods and Findings
A computer based literature search was conducted in the databases of HINARI (Health InterNetwork Access to Research Initiative), Medline and Cochrane library. Meta-analysis was performed by including randomized controlled studies that were conducted in ART experienced patients with plasma viral load above 1,000 copies HIV RNA/ml. The odds ratios and 95% confidence intervals (CI) for viral loads of <50 copies and <400 copies HIV RNA/ml at the end of the intervention were determined by the random effects model. Meta-regression, sensitivity analysis and funnel plots were done. The number of HIV-1 patients who were on either a tipranavir-ritonavir or darunavir-ritonavir based regimen and achieved viral load less than 50 copies HIV RNA/ml was significantly higher (overall OR = 3.4; 95% CI, 2.61– 4.52) than the number of HIV-1 patients who were on investigator selected boosted comparator HIV-1 protease inhibitors (CPIs-ritonavir). Similarly, the number of patients with viral load less than 400 copies HIV RNA/ml was significantly higher in either the tipranavir-ritonavir or darunavir-ritonavir based regimen treated group (overall OR = 3.0; 95% CI, 2.15 – 4.11). Meta-regression showed that the viral load reduction was independent of baseline viral load, baseline CD4 count and duration of tipranavir-ritonavir or darunavir-ritonavir based regimen.Conclusions
Tipranavir and darunavir based regimens were more effective in patients who were ART experienced and had poor viral load control. Further studies are required to determine their consistent viral load suppression effect as the duration of treatment is more prolonged. 相似文献13.
《Bioorganic & medicinal chemistry》2016,24(8):1653-1657
The antiretroviral activity of azulene derivatives was detected for the first time. A series of eighteen diversely substituted azulenes was synthesized and tested in vitro using HIV-1 based virus-like particles (VLPs) and infectious HIV-1 virus in U2OS and TZM-bl cell lines. Among the compounds tested, the 2-hydroxyazulenes demonstrated the most significant activity by inhibiting HIV-1 replication with IC50 of 2–10 and 8–20 μM for the VLPs and the infectious virus, respectively. These results indicate that azulene derivatives may be potentially useful candidates for the development of antiretroviral agents. 相似文献
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Valerian L. Kiggundu Wendy P. O'Meara Richard Musoke Fred K. Nalugoda Godfrey Kigozi Enos Baghendaghe Tom Lutalo Marion K. Achienge Steven J. Reynolds Fred Makumbi David Serwadda Ronald H. Gray Kara K. Wools-Kaloustian 《PloS one》2013,8(12)
Background
There is a paucity of data on malaria among hospitalized children in malaria endemic areas. We determined the prevalence, presentation and treatment outcomes of malaria and anemia among children in two hospitals in Rakai, Uganda.Methods
Children under five years hospitalized in Kalisizo hospital or Bikira health center in Rakai district, Uganda between May 2011 and May 2012 were enrolled and followed-up until discharge, death or referral. Data were collected on social-demographic characteristics, current and past illnesses and clinical signs and symptoms. Blood smears, hemoglobin (Hgb) levels and HIV testing were performed from finger/heel prick blood. The associations between malaria infection and other factors were estimated using log-binomial regression to estimate adjusted prevalence risk ratios (aPRR) and 95% confidence intervals (CIs), controlling for clustering at health facilities.Results
2471 children were enrolled. The most common medical presentations were fever (96.2%), cough (61.7%), vomiting (44.2%), diarrhea (20.8%), and seizures (16.0%). The prevalence of malaria parasitemia was 54.6%. Children with malaria were more likely to present with a history of fever (aPRR 2.23; CI 1.18–4.24) and seizures (aPRR 1.12; CI 1.09–1.16). Confirmed malaria was significantly lower among girls than boys (aPRR 0.92; CI 0.91–0.93), HIV infected children (aPRR 0.60 CI 0.52–0.71), and children with diarrhea (aPRR 0.76; CI 0.65–0.90). The overall prevalence of anemia (Hgb<10 g/dl) was 56.3% and severe anemia (Hgb<6 g/dL) was 17.8%. Among children with severe anemia 76.8% had malaria parasitemia, of whom 93.1% received blood transfusion. Malaria associated mortality was 0.6%.Conclusion
There was a high prevalence of malaria parasitemia and anemia among inpatient children under five years. Malaria prevention is a priority in this population. 相似文献16.
Joseph Kagaayi Ronald H. Gray Heena Brahmbhatt Godfrey Kigozi Fred Nalugoda Fred Wabwire-Mangen David Serwadda Nelson Sewankambo Veronica Ddungu Darix Ssebagala Joseph Sekasanvu Grace Kigozi Fredrick Makumbi Noah Kiwanuka Tom Lutalo Steven J. Reynolds Maria J. Wawer 《PloS one》2008,3(12)
Background
Data comparing survival of formula-fed to breast-fed infants in programmatic settings are limited. We compared mortality and HIV-free of breast and formula-fed infants born to HIV-positive mothers in a program in rural, Rakai District Uganda.Methodology/Principal Findings
One hundred eighty two infants born to HIV-positive mothers were followed at one, six and twelve months postpartum. Mothers were given infant-feeding counseling and allowed to make informed choices as to whether to formula-feed or breast-feed. Eligible mothers and infants received antiretroviral therapy (ART) if indicated. Mothers and their newborns received prophylaxis for prevention of mother-to-child HIV transmission (pMTCT) if they were not receiving ART. Infant HIV infection was detected by PCR (Roche Amplicor 1.5) during the follow-up visits. Kaplan Meier time-to-event methods were used to compare mortality and HIV-free survival. The adjusted hazard ratio (Adjusted HR) of infant HIV-free survival was estimated by Cox regression. Seventy-five infants (41%) were formula-fed while 107 (59%) were breast-fed. Exclusive breast-feeding was practiced by only 25% of breast-feeding women at one month postpartum. The cumulative 12-month probability of infant mortality was 18% (95% CI = 11%–29%) among the formula-fed compared to 3% (95% CI = 1%–9%) among the breast-fed infants (unadjusted hazard ratio (HR) = 6.1(95% CI = 1.7–21.4, P-value<0.01). There were no statistically significant differentials in HIV-free survival by feeding choice (86% in the formula-fed compared to 96% in breast-fed group (Adjusted RH = 2.8[95%CI = 0.67–11.7, P-value = 0.16]Conclusions/Significance
Formula-feeding was associated with a higher risk of infant mortality than breastfeeding in this rural population. Our findings suggest that formula-feeding should be discouraged in similar African settings. 相似文献17.
Frederikke F. R?nsholt Henrik Ullum Terese L. Katzenstein Jan Gerstoft Sisse R. Ostrowski 《PloS one》2013,8(6)
Objective
The study investigated markers of inflammation and endothelial activation in HIV infected patients after 12 years of successful combination antiretroviral treatment (cART).Methods
Inflammation and endothelial activation were assessed by measuring levels of immunoglobulins, β2-microglobulin, interleukin (IL) 8, tumor necrosis factor α (TNFα), vascular cell adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (sICAM-1), sE-Selectin, and sP-Selectin.Results
HIV infected patients had higher levels of β2-microglobulin, IL-8, TNFα, and sICAM-1 than uninfected controls, and HIV infected patients lacked correlation between platelet counts and sP-Selectin levels found in uninfected controls.Conclusion
Discrete signs of systemic and vascular inflammation persist even after very long term cART. 相似文献18.
Kigozi G Gray RH Wawer MJ Serwadda D Makumbi F Watya S Nalugoda F Kiwanuka N Moulton LH Chen MZ Sewankambo NK Wabwire-Mangen F Bacon MC Ridzon R Opendi P Sempijja V Settuba A Buwembo D Kiggundu V Anyokorit M Nkale J Kighoma N Charvat B 《PLoS medicine》2008,5(6):e116
Background
The objective of the study was to compare rates of adverse events (AEs) related to male circumcision (MC) in HIV-positive and HIV-negative men in order to provide guidance for MC programs that may provide services to HIV-infected and uninfected men.Methods and Findings
A total of 2,326 HIV-negative and 420 HIV-positive men (World Health Organization [WHO] stage I or II and CD4 counts > 350 cells/mm3) were circumcised in two separate but procedurally identical trials of MC for HIV and/or sexually transmitted infection prevention in rural Rakai, Uganda. Participants were followed at 1–2 d and 5–9 d, and at 4–6 wk, to assess surgery-related AEs, wound healing, and resumption of intercourse. AE risks and wound healing were compared in HIV-positive and HIV-negative men. Adjusted odds ratios (AdjORs) were estimated by multiple logistic regression, adjusting for baseline characteristics and postoperative resumption of sex. At enrollment, HIV-positive men were older, more likely to be married, reported more sexual partners, less condom use, and higher rates of sexually transmitted disease symptoms than HIV-negative men. Risks of moderate or severe AEs were 3.1/100 and 3.5/100 in HIV-positive and HIV-negative participants, respectively (AdjOR 0.91, 95% confidence interval [CI] 0.47–1.74). Infections were the most common AEs (2.6/100 in HIV-positive versus 3.0/100 in HIV-negative men). Risks of other complications were similar in the two groups. The proportion with completed healing by 6 wk postsurgery was 92.7% in HIV-positive men and 95.8% in HIV-negative men (p = 0.007). AEs were more common in men who resumed intercourse before wound healing compared to those who waited (AdjOR 1.56, 95% CI 1.05–2.33).Conclusions
Overall, the safety of MC was comparable in asymptomatic HIV-positive and HIV-negative men, although healing was somewhat slower among the HIV infected. All men should be strongly counseled to refrain from intercourse until full wound healing is achieved.Trial registration: http://www.ClinicalTrials.gov; for HIV-negative men, # and for HIV-positive men, # NCT00047073. NCT00047073相似文献19.
Carlum Shiu Coleen K. Cunningham Thomas Greenough Petronella Muresan Victor Sanchez-Merino Vincent Carey J. Brooks Jackson Carrie Ziemniak Lawrence Fox Marvin Belzer Stuart C. Ray Katherine Luzuriaga Deborah Persaud and the Pediatric AIDS Clinical Trials Group P Team 《Journal of virology》2009,83(19):9731-9742
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Larry W. Chang Joseph Kagaayi Gertrude Nakigozi Victor Ssempijja Arnold H. Packer David Serwadda Thomas C. Quinn Ronald H. Gray Robert C. Bollinger Steven J. Reynolds 《PloS one》2010,5(6)