Publications

CONTEXT

One of the biggest hurdles to the rapid scale-up of antiretroviral therapy in the developing world was the price of antiretroviral drugs (ARVs). Modification of an existing US Food and Drug Administration (FDA) process to expedite review and approval of generic ARVs quickly resulted in a large number of FDA-tentatively approved ARVs available for use by the US President's Emergency Plan for AIDS Relief (PEPFAR).

OBJECTIVE

To evaluate the uptake of generic ARVs among PEPFAR-supported programs in Guyana, Haiti, Vietnam, and 13 countries in Africa, and changes over time in ARV use and costs.

DESIGN, SETTING, AND PARTICIPANTS

An annual survey from 2005 to 2008 of ARVs purchased in 16 countries by PEPFAR implementing and procurement partners (organizations using PEPFAR funding to purchase ARVs).

MAIN OUTCOME MEASURES

Drug expenditures, ARV types and volumes (assessed per pack, a 1-month supply), proportion of generic procurement across years and countries, and cost savings from generic procurement.

RESULTS

ARV expenditures increased from $116.8 million (2005) to $202.2 million (2008); and procurement increased from 6.2 million to 22.1 million monthly packs. The proportion spent on generic ARVs increased from 9.17% (95% confidence interval [CI], 9.17%-9.18%) in 2005 to 76.41% (95% CI, 76.41%-76.42%) in 2008 (P < .001), and the proportion of generic packs procured increased from 14.8% (95% CI, 14.79%-14.84%) in 2005 to 89.33% (95% CI, 89.32%-89.34%) in 2008 (P < .001). In 2008, there were 8 PEPFAR programs that procured at least 90.0% of ARV packs in generic form; South Africa had the lowest generic procurement (24.7%; 95% CI, 24.6%-24.8%). Procurement of generic fixed-dose combinations increased from 33.3% (95% CI, 33.24%-33.43%) in 2005 to 42.73% (95% CI, 42.71%-42.75%) in 2008. Estimated yearly savings generated through generic ARV use were $8,108,444 in 2005, $24,940,014 in 2006, $75,645,816 in 2007, and $214,648,982 in 2008, a total estimated savings of $323,343,256.

CONCLUSION

Among PEPFAR-supported programs in 16 countries, availability of generic ARVs was associated with increased ARV procurement and substantial estimated cost savings.

Although ADAMTS13, the von Willebrand factor (VWF)-cleaving protease, is expressed in a range of tissues, the physiological significance of tissue-specific ADAMTS13 alternative splicing isoforms have yet to be clarified. Screening a panel of human tissues and cell lines revealed a spliced ADAMTS13 transcript in hepatic stellate cells and a hepatoma cell line that retains the 25th intron. A nonsense codon within the intron truncates the protease, which gains 64 novel amino acids in lieu of both CUB domains. This isoform, while retaining VWF-cleaving capability, accumulates intracellularly and its biological inaccessibility may prevent its participation in regulating haemostasis and other physiologic functions.

The basolateral amygdala is a nodal structure within a distributed and interconnected network that regulates anxiety states and anxiety-related behavior. Administration of multiple anxiogenic drugs increases cellular responses (i.e., increases c-Fos expression) in a subregion of the basolateral amygdala, but the neurochemical phenotypes of these cells are not known. The basolateral amygdala contains glutamatergic projection neurons and several populations of γ-aminobutyric acid-synthesizing (GABAergic) interneurons, including a population of parvalbumin (PV)-expressing GABAergic interneurons that co-express the excitatory 5-HT(2A) receptor. The role for these PV-expressing GABAergic interneurons in anxiety-states is unclear. In this experiment we examined the effects of multiple anxiogenic drugs including the 5-HT(2C/2A) receptor agonist m-chlorophenyl piperazine (mCPP), the adenosine receptor antagonist caffeine, the α(2)-adrenoreceptor antagonist yohimbine and the partial inverse agonist at the benzodiazepine allosteric site on the GABA(A) receptor, N-methyl-beta-carboline-3-carboxamide (FG-7142), on c-Fos expression in PV-immunoreactive (PV-ir) interneurons in subdivisions of the basolateral amygdala. All drugs with the exception of mCPP increased c-Fos expression in PV-ir neurons in the basolateral amygdaloid nucleus, anterior part (BLA). The numbers of c-Fos-immunoreactive (c-Fos-ir)/PV-ir GABAergic interneurons in the BLA were positively correlated with the numbers of c-Fos-ir serotonergic neurons in the mid-rostrocaudal dorsal raphe nucleus (DR) and with a measure of anxiety-related behavior. All four drugs increased c-Fos expression in non-PV-ir cells in most of the subdivisions of the basolateral amygdala that were sampled, compared with vehicle-injected controls. Together, these data suggest that the PV/5-HT(2A) receptor expressing GABAergic interneurons in the basolateral amygdala are part of a DR-basolateral amygdala neuronal circuit modulating anxiety-states and anxiety-related behavior.