Browsing by Subject "Infectious Diseases"

Now showing 1 - 9 of 9
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    Case report: Severe central nervous system manifestations associated with aberrant efavirenz metabolism in children: the role of CYP2B6 genetic variation
    (2015) Abrams, Elaine
    BackgroundEfavirenz, widely used as part of antiretroviral drug regimens in the treatment of paediatric human immunodeficiency virus infection, has central nervous system side effects. We describe four children presenting with serious, persistent central nervous system adverse events who were found to have elevated plasma efavirenz concentrations as a result of carrying CYP2B6 single nucleotide polymorphisms, known to play a role in the metabolism of EFV. None of the children had a CYP2B6 wildtype haplotype. We believe this is the first case of cerebellar dysfunction associated with efavirenz use to be described in children.Case presentationFour black African children, between the ages of 4 and 8years presenting between 1 and 20months post-efavirenz initiation, are described. Cerebellar dysfunction, generalised seizures and absence seizures were the range of presenting abnormalities. Plasma efavirenz levels ranged from 20-60mg/L, 5–15 times the upper limit of the suggested reference range. All abnormal central nervous system manifestations abated after efavirenz discontinuation.ConclusionEfavirenz toxicity should always be considered in human immunodeficiency virus-infected children with unexplained central nervous system abnormalities. Our findings further our understanding of the impact of genetic variants on antiretroviral pharmacokinetics in children across various ethnic groups. Screening for potential EFV-toxicity based on the CYP2B6 c.516 SNP alone, may not be adequate.
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    The characterization of a novel C-type lectin-like receptor, CLEC9A
    (2008) Huysamen, Cristal; Brown, Gordon
    Includes abstract. Includes bibliographical references (leaves 147-161).
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    Evolution of viral populations in individuals infected with single and multiple HIV subtypes : a study of HIV-1 dual infection in a high risk cohort of female bar workers from Tanzania
    (2007) Malaza, Abraham Lucky; Prof. Carolyn Williamson and Dr. Darren Martin
    The Human Immunodeficiency virus (HIV) is characterized by high replication rate and high levels of diversity resulting in numerous quasispecies that form a 'swarm' in the infected individual. HIV diversification is driven by selection pressure exerted by the host. The role of high viral diversity in disease progression in context of infection with more than one subtype (dual infection) is not elucidated. Delineating of the evolving viral diversity in dual infection will contribute to our understMding of HIV pathogenesis and thus enable for better strategies for effective therapy and vaccine development strategies. This study forms part of the HIV Superinfection Study (HISIS, www.mmrp.org) which aimed to identify the frequency of dual and superinfection in a high risk cohort of women in Mbeya, Tanzania. The Mbeya region is characterized by a highly diverse HIV epidemic where multiple HIV-1 subtypes co-circulate including A, C, and D, as well as recombinant forms. The aims of this thesis were: firstly, to investigate the distribution of HIV subtypes and recombinant forms in a cohort from Mbeya, and to determine the prevalence of HIV dual infection using the multi region hybridization assay (MHA); secondly to investigate the dynamics of viral evolution among dually infected individuals using a gel based screening assay (heteroduplex mobility assay, HMA) and sequencing, lastly the study aimed to investigate the role of point mutations and recombination on viral diversity and immune escape in a dually infected individual. The MHA was used to screen for different subtypes present in the study population (n=57). Subtypes A, C, D and their recombinants forms were detected. Subtype A accounted for 5%, C 33%, D 7% and recombinants 44%. Dual infection was detected in 11 % of individuals. AC recombinants accounted for 60% of all recombinant viral strains, ACD and CD strains accounted for approximately 12% each and AD recombinants accounted for 16%. This study provides additional information on the virus strains circulating in Tanzania. Overall these studies confirm that Tanzania harbours a complex diversity of viruses with a large proportion of the viruses being recombinant forms. The high prevalence of dual infections is clearly fuelling the generation of these recombinant viruses and it would be of interest to monitor the molecular epidemiology of the epidemic to determine if new circulating recombinant forms emerge. In a selected subset of chronically infected participants monitored over 21 months, we identified dual infection in four out of the twelve individuals. The presence of dual infections was screened for using the HMA based on the vpu and env C2C3 regions of the genome. Sequencing was employed to cpnfirm subtypes. Abstract 111 Four of the twelve women were dually infected with two distinct subtypes (A and C). The majority of single infections were by subtype C (n= 4), two were infected with subtype A, while subtype D was responsible for one infection. One individual was infected by a CD recombinant virus. Analysis of 20 randomly selected clones from different timepoints was used to determine diversity at selected timepoints. Env C2C3 region was more diverse than the vpu region with the mean DNA distances of vpu ranging from 0.9% to 8.5% compared to 0.3% and 19.5% in the env C2C3 region. Tz14 was found to harbour the most diverse viral strains with a maximum DNA distance of 12% (median 7%) in the vpu region and 14% (median 11 %) in the env C2C3 region. This individual was selected for an indepth analysis of the role of point mutations and recombination on viral evolution in dual infection. Analysis of clones from different timepoints demonstrated that dual infections were detectable in a minority of follow-up visits with only one individual having detectable dual infection at most timepoints. This emphasizes the importance of analyzing multiple time-points and that cross-sectional studies will likely underestimate the prevalence of dual infections. An analysis of the contribution of different viral variants in dual infection to overall viral burden illustrated large fluctuations of viral populations over time. However, generally the viral populations were relatively homogeneous at single time point suggesting that, while there is very high potential diversity, this diversity is largely constrained. Lastly, through full-length gene (gag and nef) sequencing we investigated positive selection, recombination patterns and screened for evidence of CTL escape in a dually infected individual (Tz14) over time (21 months). No evidence of positive selection was detected in both genes during the study period. Recombination analysis revealed that gag sequences had similar break points at time point F0 and F7. Furthermore, it was shown that none of the sequences obtained from both genes were 'pure' subtypes. Limited evidence of predicted CTL escape was observed in the nef and gag. Based on these results we postulate that viral diversity observed in these individuals is mostly a result of recombination and to a very limited extent through point mutations. This study confirms that multiple HIV -1 subtypes and recombinant viruses co-circulate in the population of Mbeya, and that there is a high prevalence of dual infections. While dually infected individuals harbour highly divergent viruses with high fluctuation of diversity over time, the diversity at a single timepoint is usually constrained. An investigation of full-length gag and nef suggests that the major mechanism of viral evolution is through recombination.
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    Immunological characterization of the HIV-tuberculosis associated immune reconstitution inflammatory syndrome
    (2011) Tadokera, Rabecca; Wilkinson, Robert J; Wilkinson, Katalin
    While the integration of anti-TB and cART therapies is associated with substantial clinical improvement in the majority of patients, HIV-Tuberculosis associated Immune Reconstitution Inflammatory Syndrome (TB-IRIS) has been shown to occur in a significant subset of these patients. TB-IRIS is an inflammatory complication of the combined treatments for HIV-1 and tuberculosis, which is being reported increasingly, particularly in areas endemic to both diseases. This work aimed to characterise the immunopathogenesis of paradoxical HIV-Tuberculosis associated immune reconstitution inflammatory syndrome.
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    Independent predictors of tuberculosis mortality in a high HIV prevalence setting: a retrospective cohort study
    (2015) Pepper, Dominique J; Schomaker, Michael; Wilkinson, Robert J; de Azevedo, Virginia; Maartens, Gary
    BackgroundIdentifying those at increased risk of death during TB treatment is a priority in resource-constrained settings. We performed this study to determine predictors of mortality during TB treatment.MethodsWe performed a retrospective analysis of a TB surveillance population in a high HIV prevalence area that was recorded in ETR.net (Electronic Tuberculosis Register). Adult TB cases initiated TB treatment from 2007 through 2009 in Khayelitsha, South Africa. Cox proportional hazards models were used to identify risk factors for death (after multiple imputations for missing data). Model selection was performed using Akaike’s Information Criterion to obtain the most relevant predictors of death.ResultsOf 16,209 adult TB cases, 851 (5.3%) died during TB treatment. In all TB cases, advancing age, co-infection with HIV, a prior history of TB and the presence of both pulmonary and extra-pulmonary TB were independently associated with an increasing hazard of death. In HIV-infected TB cases, advancing age and female gender were independently associated with an increasing hazard of death. Increasing CD4 counts and antiretroviral treatment during TB treatment were protective against death. In HIV-uninfected TB cases, advancing age was independently associated with death, whereas smear-positive disease was protective.ConclusionWe identified several independent predictors of death during TB treatment in resource-constrained settings. Our findings inform resource-constrained settings about certain subgroups of TB patients that should be targeted to improve mortality during TB treatment.
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    Inflammatory arthritis in HIV positive patients: A practical guide
    (2016) Adizie, T; Moots, R J; Hodkinson, B; French, N; Adebajo, A O
    BackgroundMusculoskeletal manifestations of the human immunodeficiency virus (HIV) have been described since the outset of the global HIV epidemic. Articular syndromes that have been described in association with HIV include HIV-associated arthropathy, seronegative spondyloarthropathies (SPA) (reactive arthritis, psoriatic arthritis (PsA) and undifferentiated SPA), rheumatoid arthritis (RA) and painful articular syndrome.MethodsWe carried out a computer-assisted search of PubMed for the medical literature from January 1981 to January 2015 using the keywords HIV, acquired immune-deficiency syndrome, rheumatic manifestations, arthritis, spondyloarthropathy, anti-TNF and disease modifying antirheumatic drugs. Only English language literature was included and only studies involving adult human subjects were assessed.ResultsThere are challenges in the management of inflammatory arthritis in patients who are HIV-positive, including difficulties in the assessment of disease activity and limited information on the safety of immunosuppressive drugs in these individuals.ConclusionsThis review focuses on the clinical characteristics of the inflammatory articular syndromes that have been described in association with HIV infection and discusses the therapeutic options for these patients.
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    Outcome of AIDS-associated cryptococcal meningitis initially treated with 200 mg/day or 400 mg/day of fluconazole
    (BioMed Central Ltd, 2006) Schaars, CF; Meintjes, GA; Morroni, C; Post, FA; Maartens, G
    BACKGROUND:AIDS-associated cryptococcal meningitis has a high mortality. Fluconazole was the only systemic antifungal therapy available in our centre. From 1999-2001 we used low-dose fluconazole (200 mg daily initially), and did not offer therapy to patients perceived to have poor prognoses. In 2001 donated fluconazole became available, allowing us to use standard doses (400 mg daily initially). Antiretroviral therapy was not available during the study period. METHODS: Retrospective chart review of adult patients before and after the fluconazole donation. RESULTS: 205 patients fulfilled the inclusion criteria, 77 before and 128 after the donation. Following the donation fewer patients received no antifungal treatment (5% vs 19%, p = 0.002), and more patients received standard-dose fluconazole (90% vs 6%, p < 0.001). In-hospital mortality was 25%. Impaired consciousness, no antifungal treatment received and cerebrospinal fluid antigen titre > 1,000 were independent predictors of in-hospital mortality. Concomitant rifampicin did not affect in-hospital survival. Thirteen patients were referred to the tertiary referral hospital and received initial treatment with amphotericin B for a mean of 6 days - their in-hospital survival was not different from patients who received only fluconazole (p = 0.9). Kaplan-Meier analysis showed no differences in length of survival by initial treatment with standard or low doses of fluconazole (p = 0.27 log rank test); median survival was 76 and 82 days respectively. CONCLUSION: Outcome of AIDS-associated cryptococcal meningitis is similar with low or standard doses of fluconazole. The early mortality is high. Initial therapy with amphotericin B and other measures may be needed to improve outcome.
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    Sensory neuropathy and metabolic risk factors in human immune deficiency virus infected South Africans receiving protease inhibitors
    (2015) Vermaak, John-Randel; Dave, Joel A; Levitt, Naomi; Heckmann, Jeannine M
    BackgroundProtease inhibitors (PI)s have been associated with distal sensory polyneuropathy (DSP) and metabolic complications in high-income countries. No data exist in Africans where second-line antiretroviral therapy (ART) often include PIs.MethodWe performed a cross-sectional study to assess the DSP frequency and metabolic risk factors in community-based South Africans taking ritonavir-boosted lopinavir as PI. Examination findings categorized subjects as having DSP (≥1 neuropathic sign) or symptomatic DSP [DSP with symptom(s)]. Fasting-state glucose and lipid profiles were assessed. We compared the ritonavir/lopinavir-group to a nested group on first-line ART [dideoxy-nucleoside reverse transcriptase inhibitors (d-drugs)] selected from a dataset collected at the same time and matched for d-drug exposure.ResultsThe ritonavir/lopinavir-group (n=86) consisted predominantly of women (84%) with a median age of 36years (IQR 32–41). The median current CD4+ count was 489cells/μL (IQR 291–665). The median exposure time to ritonavir/lopinavir was 18months (IQR 10–26) and to d-drugs, 24months (IQR 16–38). DSP was present in 78% and symptomatic DSP in 48%; symptoms were most frequently of moderate intensity. Only age independently associated with DSP and symptomatic DSP (p=0.08 and p=0.04, respectively). None of the metabolic syndrome components showed associations with DSP or symptomatic DSP despite a trend towards hypertriglyceridemia overall. The ritonavir/lopinavir-group had less DSP compared to the d-drug only group (p=0.002) but the frequency of symptomatic DSP was similar (p=0.49).ConclusionRitonavir-boosted lopinavir did not add additional risk to developing DSP in this community-based African cohort after a median of 18months on second-line ART.Electronic supplementary materialThe online version of this article (doi:10.1186/s12981-015-0073-8) contains supplementary material, which is available to authorized users.
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    Third-line antiretroviral therapy in Africa: effectiveness in a Southern African retrospective cohort study
    (2015) Meintjes, Graeme; Dunn, Liezl; Coetsee, Marla; Hislop, Michael; Leisegang, Rory; Regensberg, Leon; Maartens, Gary
    Background An increasing number of patients in Africa are experiencing virologic failure on second-line antiretroviral therapy (ART) and those who develop resistance to protease inhibitors (PI) will require third-line ART, but no data on the outcomes of third-line are available from the region. We assessed the virologic outcomes and survival of patients started on salvage ART in a Southern African private sector disease management programme.Methods Retrospective observational cohort study with linkage to the national death register. Adults (≥18years) who started salvage ART between July 2007 and December 2011 were included. Salvage ART was defined by inclusion of darunavir or tipranavir in an ART regimen after having failed another PI. For Kaplan–Meier (KM) analysis, patients were followed up until event, or censored at death (only for virologic outcomes), leaving the programme, or April 2014.Results152 patients were included. Subtype was known for 113 patients: 111 (98%) were infected with subtype C. All 152 had a genotype resistance test demonstrating major PI resistance mutations. Salvage drugs included were: darunavir/ritonavir (n=149), tipranavir/ritonavir (n=3), raltegravir (n=58), and etravirine (n=8). Median follow-up was 2.5years (IQR=1.5–3.3). 82.9% achieved a viral load ≤400 copies/ml and 71.1% ≤50 copies/ml. By the end of the study 17 (11.2%) of the patients had died. The KM estimate of cumulative survival was 87.2% at 2000days.ConclusionsVirologic suppression was comparable to that demonstrated in clinical trials and observational studies of salvage ART drugs conducted in other regions. Few deaths occurred during short term follow-up. Third-line regimens for patients with multidrug resistant subtype C HIV in Africa are virologically and clinically effective.