Raveen Parboosing

Gestational Influenza and Bipolar Disorder in Adult Offspring

IMPORTANCE Gestational influenza has been associated previously with schizophrenia in offspring, but the relationship between this exposure and bipolar disorder (BD) is unclear. The identification of gestational influenza as a risk factor for BD may have potential for preventive approaches. OBJECTIVE To test the hypothesis that maternal influenza during pregnancy is related to BD among offspring. DESIGN Nested case-control study of a population-based birth cohort from the Child Health and Development Study (CHDS). From January 1, 1959, through December 31, 1966, the CHDS recruited nearly all pregnant women receiving obstetric care from the Kaiser Permanente Medical Care Plan, Northern California Region (KPNC). Data on treated maternal influenza from the CHDS were used. Potential cases with BD from the cohort were identified by database linkages of identifiers among the CHDS, Kaiser Permanente database, and a large county health care database; by a mailed questionnaire to the CHDS cohort with subsequent interviews; and from an earlier psychiatric follow-up study on this birth cohort. SETTING The CHDS, Kaiser Permanente, and county health care databases. PARTICIPANTS Cases of BD (n = 92) confirmed by structured research interviews and consensus diagnosis among the 214 subjects (48% of those ascertained) who participated and control subjects (n = 722) matched on date of birth, sex, and membership in KPNC or residence in Alameda County. EXPOSURES Influenza. MAIN OUTCOME AND MEASURES Bipolar I or II disorder, BD not otherwise specified, or BD with psychotic features. RESULTS We found a significant, nearly 4-fold increase in the risk of BD (odds ratio, 3.82 [95% CI, 1.58-9.24; P = .003]) after exposure to maternal influenza at any time during pregnancy. The findings were not confounded by maternal age, race, educational level, gestational age at birth, and maternal psychiatric disorders. CONCLUSIONS AND RELEVANCE Maternal influenza may be a risk factor for BD. Although replication is required, the findings suggest that prevention of maternal influenza during pregnancy may reduce the risk of BD.

Defining immune reconstitution inflammatory syndrome: evaluation of expert opinion versus 2 case definitions in a South African cohort.

BACKGROUND There is no validated case definition for human immunodeficiency virus-associated immune reconstitution inflammatory syndrome (IRIS). We measured the level of agreement of 2 published case definitions (hereafter referred to as CD1 and CD2) with expert opinion in a prospective cohort of patients who were starting antiretroviral therapy in South Africa. METHODS A total of 498 adult patients were monitored for the first 6 months of antiretroviral therapy. All new or worsening clinical events were reviewed by 2 investigators and classified on the basis of expert opinion, CD1, and CD2. Events were categorized according to whether they were paradoxical or unmasking in presentation. We measured positive, negative, and chance-corrected agreement (kappa) with expert opinion for CD1 and CD2, and reviewed areas of disagreement. RESULTS A total of 620 clinical events were recorded, of which, on the basis of expert opinion, 144 (23.2%) were defined as probable IRIS and 112 (18.1%) were defined as possible IRIS. Of the 144 probable IRIS events, 93 (64.6%) were unmasking in presentation, 99 (68.8%) were associated with dermatological or orogenital disease, and 45 (31.3%) were associated with tuberculosis or major opportunistic infections. Of the 620 clinical events recorded, 41 (6.6%) were classified as IRIS on the basis of CD1, and 156 (25.2%) were classified as IRIS on the basis of CD2. Positive agreement between CD1 and expert opinion was low for both unmasking (17.2%; kappa = 0.24) and paradoxical events (37.3%; kappa = 0.43), mainly because 1 major criterion requires IRIS to be atypical and either an opportunistic infection or a tumor, although negative agreement was >98%. In contrast, CD2 had good positive agreement (>75% for most event types), with a kappa value of 0.75 for paradoxical and 0.62 for unmasking. CONCLUSIONS CD2 agreed well with expert opinion, with additional clinical events, such as arthropathy and inflammatory dermatoses, being classified as IRIS and added to CD2. We propose revised case definitions for both paradoxical and unmasking IRIS.

Nanotechnology and the Treatment of HIV Infection

Suboptimal adherence, toxicity, drug resistance and viral reservoirs make the lifelong treatment of HIV infection challenging. The emerging field of nanotechnology may play an important role in addressing these challenges by creating drugs that possess pharmacological advantages arising out of unique phenomena that occur at the “nano” scale. At these dimensions, particles have physicochemical properties that are distinct from those of bulk materials or single molecules or atoms. In this review, basic concepts and terms in nanotechnology are defined, and examples are provided of how nanopharmaceuticals such as nanocrystals, nanocapsules, nanoparticles, solid lipid nanoparticles, nanocarriers, micelles, liposomes and dendrimers have been investigated as potential anti-HIV therapies. Such drugs may, for example, be used to optimize the pharmacological characteristics of known antiretrovirals, deliver anti-HIV nucleic acids into infected cells or achieve targeted delivery of antivirals to the immune system, brain or latent reservoirs. Also, nanopharmaceuticals themselves may possess anti-HIV activity. However several hurdles remain, including toxicity, unwanted biological interactions and the difficulty and cost of large-scale synthesis of nanopharmaceuticals.

Incidence, clinical spectrum, risk factors and impact of HIV-associated immune reconstitution inflammatory syndrome in South Africa.

Background Immune reconstitution inflammatory syndrome (IRIS) is a widely recognised complication of antiretroviral therapy (ART), but there are still limited data from resource-limited settings. Our objective was to characterize the incidence, clinical spectrum, risk factors and contribution to mortality of IRIS in two urban ART clinics in South Africa. Methods and Findings 498 adults initiating ART in Durban, South Africa were followed prospectively for 24 weeks. IRIS diagnosis was based on consensus expert opinion, and classified by mode of presentation (paradoxical worsening of known opportunistic infection [OI] or unmasking of subclinical disease). 114 patients (22.9%) developed IRIS (36% paradoxical, 64% unmasking). Mucocutaneous conditions accounted for 68% of IRIS events, mainly folliculitis, warts, genital ulcers and herpes zoster. Tuberculosis (TB) accounted for 25% of IRIS events. 18/135 (13.3%) patients with major pre-ART OIs (e.g. TB, cryptococcosis) developed paradoxical IRIS related to the same OI. Risk factors for this type of IRIS were baseline viral load >5.5 vs. <4.5 log10 (adjusted hazard ratio 7.23; 95% confidence interval 1.35–38.76) and ≤30 vs. >30 days of OI treatment prior to ART (2.66; 1.16–6.09). Unmasking IRIS related to major OIs occurred in 25/498 patients (5.0%), and risk factors for this type of IRIS were baseline C-reactive protein ≥25 vs. <25 mg/L (2.77; 1.31–5.85), haemoglobin <10 vs. >12 g/dL (3.36; 1.32–8.52), ≥10% vs. <10% weight loss prior to ART (2.31; 1.05–5.11) and mediastinal lymphadenopathy on pre-ART chest x-ray (9.15; 4.10–20.42). IRIS accounted for 6/25 (24%) deaths, 13/65 (20%) hospitalizations and 10/35 (29%) ART interruptions or discontinuations. Conclusion IRIS occurred in almost one quarter of patients initiating ART, and accounted for one quarter of deaths in the first 6 months. Priority strategies to reduce IRIS-associated morbidity and mortality in ART programmes include earlier ART initiation before onset of advanced immunodeficiency, improved pre-ART screening for TB and cryptococcal infection, optimization of OI therapy prior to ART initiation, more intensive clinical monitoring in initial weeks of ART, and education of health care workers and patients about IRIS.

Hepatitis C virus seropositivity in a South African Cohort of HIV co-infected, ARV naïve patients is associated with renal insufficiency and increased mortality†

HIV is known to affect the epidemiology, transmission, pathogenesis and natural history of HCV infection whilst studies on the effects of HCV on HIV have shown conflicting results and are confounded by the influence of intravenous drug use and antiretroviral therapy. This study was conducted in KwaZulu‐Natal Province in South Africa where HIV is predominantly a sexually transmitted infection. Intravenous drug use is rare in this region and the study population was naïve to antiretroviral therapy. For this study, specimens from selected sentinel sites submitted to a central laboratory for routine HIV testing were screened for anti‐HCV IgG antibodies. HIV positive HCV‐positive patients were compared to HIV‐positive HCV‐negative patients in a subgroup of patients within this cohort in order to determine if HCV sero‐prevalence was associated with clinical outcomes in a linked anonymous retrospective chart survey. The prevalence of HCV was 6.4% and that of HIV, 40.2% (n = 1,937). There was a significantly higher prevalence of HCV among HIV infected patients as compared to HIV negative patients (13.4% vs. 1.73% respectively) (n = 1,937, P < 0.001). HCV‐HIV co‐infected patients had significantly increased mortality (8.3 vs. 21%) (n = 162, P < 0.02). A significant association was found between HCV serostatus and abnormal urea levels (15.4 vs. 7.3 mmol/L, n = 134, P < 0.001) and creatinine levels (252.2 vs. 144.4 µmol/L, n = 134, P < 0.01). This study has found that hepatitis C co‐infection is more common in HIV positive individuals and is associated with an increased mortality and renal morbidity. J. Med. Virol. 80:1530–1536, 2008.

Resistance to antiretroviral drugs in newly diagnosed, young treatment‐naïve HIV‐positive pregnant women in the province of KwaZulu‐Natal, South Africa

In 2004, KwaZulu‐Natal initiated one of the worlds largest HIV/AIDS treatment programs. Studies in South Africa have shown that patients on antiretroviral therapy (ART) develop rapidly and transmit drug resistant mutations. Since resistance testing is not widely available in Kwazulu‐Natal, the Department of Health conducted the first HIV drug resistance (HIVDR) threshold survey in 2005, which did not identify any mutations associated with HIVDR. The objective of this study was to conduct a follow‐up threshold survey to update the information on HIVDR. This study was conducted in 2009 in five antenatal care sites in Kwazulu‐Natal using the HIVDR threshold survey method developed by WHO. Two hundred and thirteen newly‐diagnosed HIV positive, drug‐naïve primigravidae, less than 22 years of age were included in the survey. Of the 82 HIV positive specimens, 17 had insufficient volume for genotyping and, of the remaining 65, 47 were genotyped sequentially. Drug resistance was identified by sequencing the HIV‐1 pol gene, using the ViroSeq® HIV‐1 genotyping system v2.0. Of the 47 samples that were genotyped, only one presented with a K103N mutation, which equates to a prevalence of transmitted HIVDR of <5%. The low prevalence of transmitted HIVDR is in keeping with statistical models of the early stages of ART rollout. As ART coverage is increasing continuously, there is a need to ensure that vigilance of HIVDR continues so that the emergence and spread of HIVDR is minimized. This survey should be repeated in 2011, in accordance with WHO guidelines. J. Med. Virol. 83:1508–1513, 2011.

NOTA: a potent metallo-β-lactamase inhibitor

Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, Durban, South Africa; Antimicrobial Research Unit, School of Health Sciences, University of KwaZulu-Natal, Durban, South Africa; Biomedical Resource Unit, Westville Campus, University of KwaZulu-Natal, Durban, South Africa; Department of Virology, National Health Laboratory Service/University of KwaZulu-Natal, c/o Inkosi Albert Luthuli Central Hospital, Durban, South Africa; Science for Life Laboratory, Drug Discovery and Development Platform, and Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden

Reduction in perinatal HIV infections in KwaZulu-Natal, South Africa, in the era of more effective prevention of mother to child transmission interventions (2004-2012).

Objective:To describe a trend in perinatal HIV transmission associated with the implementation of rapidly changing prevention of mother to child transmission (PMTCT) interventions from 2004 to 2012. Method:Retrospective analysis of infant HIV polymerase chain reaction results of infants from 2004 to 2012 archived from a Laboratory Information System. Setting:KwaZulu-Natal, South Africa. Main Outcome Measure:HIV infection in infants aged 4–8 weeks. Results:The proportion of 4- to 8-week-old infants who tested HIV polymerase chain reaction positive decreased significantly (P < 0.0001) from 27.5% in 2004 to 2.9% in 2012. The reduction rates in perinatal HIV infections in 4- to 8-week-old HIV-exposed infants decreased significantly (P < 0.0001) by 48.7% following single-dose nevirapine (sdNVP) (2005 to April 2008), 68.4% with zidovudine from 28 weeks and sdNVP together with triple antiretroviral therapy for women with CD4+ cell count < 200 cells/mm3 (May 2008–April 2010), and 89.5% with zidovudine from 14 weeks, sdNVP, and triple antiretroviral therapy for women with CD4+ cell count < 350 cells/mm3 (May 2010–December 2012). Conclusions:We show an almost 10-fold reduction in mother to child transmission from 2004 to 2012 in infants aged 4–8 weeks during a rapid implementation of more complex and robust PMTCT interventions. The significant reductions in mother to child transmission in the South African PMTCT program are encouraging for a middle-income country with the second highest antenatal HIV prevalence in the world.

Synthesis, 68Ga-radiolabeling, and preliminary in vivo assessment of a depsipeptide-derived compound as a potential PET/CT infection imaging agent.

Noninvasive imaging is a powerful tool for early diagnosis and monitoring of various disease processes, such as infections. An alarming shortage of infection-selective radiopharmaceuticals exists for overcoming the diagnostic limitations with unspecific tracers such as 67/68Ga-citrate or 18F-FDG. We report here TBIA101, an antimicrobial peptide derivative that was conjugated to DOTA and radiolabeled with 68Ga for a subsequent in vitro assessment and in vivo infection imaging using Escherichia coli-bearing mice by targeting bacterial lipopolysaccharides with PET/CT. Following DOTA-conjugation, the compound was verified for its cytotoxic and bacterial binding behaviour and compound stability, followed by 68Gallium-radiolabeling. µPET/CT using 68Ga-DOTA-TBIA101 was employed to detect muscular E. coli-infection in BALB/c mice, as warranted by the in vitro results. 68Ga-DOTA-TBIA101-PET detected E. coli-infected muscle tissue (SUV = 1.3–2.4) > noninfected thighs (P = 0.322) > forearm muscles (P = 0.092) > background (P = 0.021) in the same animal. Normalization of the infected thigh muscle to reference tissue showed a ratio of 3.0 ± 0.8 and a ratio of 2.3 ± 0.6 compared to the identical healthy tissue. The majority of the activity was cleared by renal excretion. The latter findings warrant further preclinical imaging studies of greater depth, as the DOTA-conjugation did not compromise the TBIA101s capacity as targeting vector.

Sodium valproate and highly active antiretroviral therapy in HIV positive patients who develop new onset seizures

Recurrent seizures may occur in up to 11% of HIV positive patients. The aetiology of the seizures includes opportunistic infections, neoplasia, HIV itself, metabolic derangements and drugs. Apart from treating the cause of the seizures, the challenge is to use the appropriate anticonvulsant drug (AED) to avoid potentially adverse drug-drug interactions in patients who are on concurrent highly active antiretroviral therapy (HAART). Initial recommendations were that the newer AEDs should preferably be used because of their simpler pharmacokinetics. We report on our experience with the use sodium valproate (SV) in eight patients who were on concurrent HAART. There were two males and six females with a mean age of 34.1 years. The mean dose of SV was 1075 mg per day. Seizure control was excellent, the CD4 count improved and there was successful viral suppression in all patients. This small study showed that SV was safe and effective. It is also relatively inexpensive compared to the newer AEDs - an important consideration in resource poor settings.