Prognostic importance of initial response in HIV-1 infected patients starting potent antiretroviral therapy: analysis of prospective studies

The Antiretroviral Therapy (ART) Cohort Collaboration*

*Writing committee listed at end of report. Members of study groups are listed in webappendix 1 (http://www.image.thelancet.com/extras/03art2393webappendix1.pdf)

Correspondence to: Prof Matthias Egger, Department of Social and Preventive Medicine, University of Bern, Finkenhubelweg 11, CH-3012 Bern, Switzerland (e-mail:egger@ispm.unibe.ch)

Summary

Background

We examined whether the initial virological and immunological response to highly active antiretroviral treatment (HAART) is prognostic in patients with HIV-1 who start HAART.

Methods

We analysed 13 cohort studies from Europe and North America including 9323 adult treatment-naive patients who were starting HAART with a combination of at least three drugs. We modelled clinical progression from month 6 after starting HAART, taking into account CD4 count and HIV-1 RNA measured at baseline and 6 months.

Findings

During 13 408 years of follow-up 152 patients died and 874 developed AIDS or died. Compared with patients who had a 6-month CD4 count of fewer than 25 cells/µL, adjusted hazard ratios for AIDS or death were 0·55 (95%CI 0·32-0·96) for 25-49 cells/µL, 0·62 (0·40-0·96) for 50-99 cells/µL, 0·42 (0·28-0·64) for 100-199 cells/µL, 0·25 (0·16-0·38) for 200-349 cells/µL, and 0·18 (0·11-0·29) for 350 or more cells/µL at 6 months. Compared with patients who had a 6-month HIV-1 RNA of 100 000 copies/mL or greater, adjusted hazard ratios for AIDS or death were 0·59 (0·41-0·86) for 10000-99999 copies/mL, 0·42 (0·29-0·61) for 500-9999 copies/mL, and 0·29 (0·21-0·39) for 6-month HIV-1 RNA of 500 copies/mL or fewer. Baseline CD4 and HIV-1 RNA were not associated with progression after controlling for 6-month concentrations. The probability of progression at 3 years ranged from 2·4% in the patients in the lowest-risk stratum to 83% in patients in the highest-risk stratum.

Interpretation

At 6 months after starting HAART, the current CD4 cell count and viral load, but not values at baseline, are strongly associated with subsequent disease progression. Our findings should inform guidelines on when to modify HAART.

Lancet 2003; 362: 679-86

Humanised yeast produce healing proteins

Engineered cells might make cheaper medicines.
29 August 2003

HELEN PEARSON

Yeast cells grow faster and more easily than mammalian cells
© SPL

A humanised yeast that pumps out medicinal proteins could simplify drug manufacture.

Human proteins are increasingly used as medicines - erythropoietin for example, bolsters flagging red blood cells after cancer. But many, called glycoproteins, must be reaped from mammalian cells if they are to contain vital sugar molecules. This harvesting is expensive and inefficient.

So Tillman Gerngross of Dartmouth College in Hanover, New Hampshire and his coworkers have tweaked yeast cells to attach human sugar molecules to a protein. "You put in a human gene and it'll make a human protein," he says.

Since yeast grow faster and need less tending than mammalian cells, they could make the manufacture of human proteins cheaper and easier. Already human insulin for diabetics, which does not need added sugars, is brewed from yeast in this way.

One day, production of human antibodies such as herceptin for breast cancer, plus countless others under development, might switch into yeast. "It's a huge advance," says Carolyn Bertozzi who studies glycoproteins at the University of California at Berkeley. "They've done a heroic engineering experiment".

Yeast-assembled proteins may also be safer. Yeast make only one shape of glycoprotein, whereas mammalian cells churn out a cocktail, explains biochemist Laura Kiessling of the University of Wisconsin, Madison. Each variant may stick to cells or breakdown differently so that the mixture is less predictable.

No added sugar

Enzymes in human cells attach sugars to new proteins, then prune and elaborate on them. Because yeast affix different sugars to their glycoproteins, their molecules normally trigger an immune reaction in people. Bacteria add no sugars at all.

To create human-style glycoproteins, some researchers are breeding genetically engineered plants or cattle that might secrete the molecules in their leaves or milk. Others are attempting to humanize insect or bacterial cells or are synthesising the proteins via clever chemistry.

Gerngross is the co-founder of a company called GlycoFi that hopes to capitalize on the yeast. His team has already humanised it even further, he claims, by engineering strains to carry extra enzymes that tweak the sugars into a more final human form.

References

1. Hamilton, S. R. et al. Production of complex human glycoproteins in yeast. Science, 301, 1244 - 1246 (2003).|Homepage|


© Nature News Service / Macmillan Magazines Ltd 2003