HIV prevalence and the cascade of care in five South African correctional facilities.

BACKGROUND: South Africa is home to the world's largest HIV epidemic. Throughout the world, incarcerated individuals have a higher prevalence of HIV than the general public, and South Africa has one of the highest rates of incarceration in sub-Saharan Africa. In spite of this, little has been published about the burden of HIV and how care is delivered in South African correctional facilities. OBJECTIVE: To estimate the prevalence of people living with HIV and identify initiation and retention in the HIV cascade of care across five correctional facilities. METHODS: Cross-sectional retrospective analysis of 30,571 adult inmates who participated in a tuberculosis screening and HIV counseling and testing campaign in South African correctional facilities (January 1, 2014-January 31, 2015). Descriptive statistics were used to estimate the proportion and 95% confidence intervals of HIV. Proportions of persons retained and lost at each step in the HIV cascade of care under this intervention were calculated. Poisson regression with robust variance estimates were used, and clustering by facility was accounted for in all analyses. RESULTS: Results of the screening campaign found previously undiagnosed HIV among 13.0% of those consenting to screening, with a total estimated HIV prevalence of 17.7% (n = 3,184, 95% CI: 17.2-18.3%) in the sample. When examining the overall cascade of care, 48.3% of those with HIV initiated care, and overall 45.6% of persons who entered care qualified for ART initiated treatment. A Poisson regression accounting for clustering by facility found HIV high risk groups within the population such as women (aRR = 1.72, 95% CI: 1.57, 1.89), those over 35 years of age (aRR = 2.43, 95% CI: 1.53, 3.85), and people incarcerated less than one year (aRR = 1.41, 95% CI: 1.19, 1.67). CONCLUSION: In this setting, routine screening is recommended, and measures are needed to ensure that persons diagnosed are adequately linked to and retained in care.

Quinoline antimalarials containing a dibemethin group are active against chloroquinone-resistant Plasmodium falciparum and inhibit chloroquine transport via the P. falciparum chloroquine-resistance transporter (PfCRT).

A series of 4-amino-7-chloroquinolines with dibenzylmethylamine (dibemethin) side chains were shown to inhibit synthetic hemozoin formation. These compounds were equally active against cultures of chloroquine-sensitive (D10) and chloroquine-resistant (K1) Plasmodium falciparum. The most active compound had an IC(50) value comparable to that of chloroquine, and its potency was undiminished when tested in three additional chloroquine-resistant strains. The three most active compounds exhibited little or no cytotoxicity in a mammalian cell line. When tested in vivo against mouse malaria via oral administration, two of the dibemethin derivatives reduced parasitemia by over 99%, with mice treated at 100 mg/kg surviving the full length of the experiment. Three of the compounds were also shown to inhibit chloroquine transport via the parasite's chloroquine-resistance transporter (PfCRT) in a Xenopus oocyte expression system. This constitutes the first example of a dual-function antimalarial for which the ability to inhibit both hemozoin formation and PfCRT has been demonstrated directly.

A series of structurally simple chloroquine chemosensitizing dibemethin derivatives that inhibit chloroquine transport by PfCRT.

A series of 12 new dibemethin (N-benzyl-N-methyl-1-phenylmethanamine) derivatives bearing an N-aminomethyl group attached to the one phenyl ring and an H, Cl, OCH3 or N(CH3)2 group on the other have been synthesized. These compounds all showed strong chloroquine chemosensitizing activity, comparable to verapamil, when present at 1 µM in an in vitro culture of the chloroquine-resistant W2 strain of the human malaria parasite, Plasmodium falciparum. Their N-formylated derivatives also exhibited resistance-reversing activity, but only at substantially higher IC10 concentrations. A number of the dibemethin derivatives were shown to inhibit chloroquine transport via the parasite's 'chloroquine resistance transporter' (PfCRT) in a Xenopus laevis oocyte expression system. The reduced resistance-reversing activity of the formylated compounds relative to their free amine counterparts can probably be ascribed to two factors: decreased accumulation of the formylated dibemethins within the parasite's internal digestive vacuole (believed to be the site of action of chloroquine), and a reduced ability to inhibit PfCRT. The resistance-reversing activity of the compounds described here demonstrates that the amino group need not be attached to the two aromatic rings via a three or four carbon chain as has been suggested by previous QSAR studies. These compounds may be useful as potential side chains for attaching to a 4,7-dichloroquinoline group in order to generate new resistance-reversing chloroquine analogues with inherent antimalarial activity.

Interference with hemozoin formation represents an important mechanism of schistosomicidal action of antimalarial quinoline methanols.

BACKGROUND: The parasitic trematode Schistosoma mansoni is one of the major causative agents of human schistosomiasis, which afflicts 200 million people worldwide. Praziquantel remains the main drug used for schistosomiasis treatment, and reliance on the single therapy has been prompting the search for new therapeutic compounds against this disease. Our group has demonstrated that heme crystallization into hemozoin (Hz) within the S. mansoni gut is a major heme detoxification route with lipid droplets involved in this process and acting as a potential chemotherapeutical target. In the present work, we investigated the effects of three antimalarial compounds, quinine (QN), quinidine (QND) and quinacrine (QCR) in a murine schistosomiasis model by using a combination of biochemical, cell biology and molecular biology approaches. METHODOLOGY/PRINCIPAL FINDINGS: Treatment of S. mansoni-infected female Swiss mice with daily intraperitoneal injections of QN, and QND (75 mg/kg/day) from the 11(th) to 17(th) day after infection caused significant decreases in worm burden (39%-61%) and egg production (42%-98%). Hz formation was significantly inhibited (40%-65%) in female worms recovered from QN- and QND-treated mice and correlated with reduction in the female worm burden. We also observed that QN treatment promoted remarkable ultrastructural changes in male and female worms, particularly in the gut epithelium and reduced the granulomatous reaction to parasite eggs trapped in the liver. Microarray gene expression analysis indicated that QN treatment increased the expression of transcripts related to musculature, protein synthesis and repair mechanisms. CONCLUSIONS: The overall significant reduction in several disease burden parameters by the antimalarial quinoline methanols indicates that interference with Hz formation in S. mansoni represents an important mechanism of schistosomicidal action of these compounds and points out the heme crystallization process as a valid chemotherapeutic target to treat schistosomiasis.