Patients have cells 'HIV proofed' in first step to a cure
The therapy, which could be the first step towards a cure for HIV infection, produced significant CD4 count increases in people with persistently low counts, changing their immune system to one more like that of someone without HIV.
Jay Lalezari and colleagues used enzymes called zinc finger nucleases to disable the gene producing CCR5, a molecule on the surface of some immune cells. HIV-1, the most common type of HIV, can only infect a cell with CCR5 molecules.
T-cells, an immune cell type that includes CD4 cells, were removed from six people, and infected in the test tube with an artificial virus containing zinc finger nucleases, which physically ‘snipped out’ the CCR5 molecule. The T-cells were re-introduced into the patients. After 90 days, up to 7% of CD4 cells showed the CCR5 deletion.
The altered CD4 cells embedded and reproduced similarly to normal T-cells. Five people experienced significant, sustained CD4 increases, averaging about 200 cells/mm3.
The CD4 to CD8 cell ratio, typically reversed in people with HIV, normalised in five participants.
All six were on HIV treatment. The next study will try the approach with people not on treatment to see if making T-cells resistant to infection will break the chain of viral production and reduce HIV viral loads.
If this happens, protected cells would proliferate while susceptible cells would be infected with HIV and die. This could lead to a ‘functional cure’, at least in people who only have virus that links to CCR5.
New drug targets first step in infection
HIV infection has three stages. The virus catches hold of the CD4 molecules on immune cells. It then draws closer to the cell surface and links with co-receptor molecules (CCR5 or CXCR4). Finally, it fuses with the cell membrane and releases genetic material into the cell. The drug maraviroc (Celsentri) targets the second step and T-20 (enfuvirtide, Fuzeon) inhibits the third. BMS-663068 is a CD4 blocker, preventing the first step. It binds to a glycoprotein (gp120) in the HIV-1 ‘envelope’, interfering with its attachment to the CD4 receptor.
The first study of the drug involved 50 people with clade B HIV. They had average CD4 counts of 432 cells/mm3 and viral loads of at least 5000 copies/ml. About two-thirds were treatment-naive; the other third had been off HIV treatment for at least eight weeks.
BMS-663068 produced forty- to sixty-fold declines in viral load over the eight days of the study, andCD4 cell gains ranging from 28 to 106 cells/mm3.
Results indicated it could be taken once a day and that ritonavir boosting was unnecessary. The most frequent side-effects were headache and skin rash, mostly mild.
Abacavir works less well in patients with low CD4 counts
A study presented at CROI was a head-to-head comparison of treatment failure rates in patients taking abacavir/3TC (Kivexa) as first-line therapy and tenofovir/FTC (Truvada). It found Kivexa had a higher treatment failure rate in patients starting with high viral loads, low CD4 counts, or both, whereas all patients did equally well on Truvada.3
This study is important because tenofovir, either alone (Viread), as Truvada or, with efavirenz, as the one-pill Atripla, is the most widely prescribed HIV drug in the developed world. For cost reasons, however, London’s HIV commissioners have decided to start new patients on Kivexa (see HIV drug prescribing in London) unless contra-indicated.
Some studies have found that people taking abacavir are more likely to have heart attacks, though others disagree; other studies have found that people with high viral loads (over 100,000 copies/ml) are less likely to see their viral load fall to an undetectable level.
The A5202 study put 1857 people new to therapy on either Kivexa plus a placebo Truvada pill or on Truvada plus Kivexa placebo (also randomising them to efavirenz or atazanavir).
Average CD4 count on starting was 230 cells/mm3, with 43% having a CD4 count below 200 and 18% below 50. Average viral load was 50,000 copies/ml and 25% had over 100,000 copies/ml.
Broadly speaking, treatment failure rates in patients on Truvada were similar regardless of CD4 count or viral load. In contrast, rates in patients on Kivexa differed across treatment arms. They were similar to rates with Truvada – approximately 20% – in people with viral loads below 100,000 copies/ml and CD4 counts over 50 cells/mm3; only these people should be prescribed Kivexa under the new London arrangements.
Failure rates were higher, however, in people with baseline viral loads over 100,000 copies/ml, averaging 25% in those with CD4 counts over 50 cells/mm3. A new finding was especially high failure rates with Kivexa in people who started with a CD4 count below 50 cells/mm3, regardless of viral load (35 to 40%) – so 2.44 times higher than people with CD4 counts above 50.
In analysis that took account of factors like age and race, Kivexa patients with CD4 counts under 50 remained 75% more likely to fail treatment, although this became just statistically non-significant.
Does diagnosis change risk behaviour? Studies disagree
Two studies presented at CROI found that gay men diagnosed with HIV reduced the amount of sex they had that could pass on infection. Although one study (from San Francisco)4 found that the reduction in risk behaviour was profound and long-lasting, the other (from Amsterdam)5 showed it was comparatively slight and short-lived.
The Amsterdam study followed 206 gay men, monitoring the sexual risk behaviour of those who acquired HIV for four years before and four after diagnosis. The San Francisco study followed the risk behaviour of its 237 subjects from the date of diagnosis, for 12 years.
In Amsterdam, HIV diagnosis produced an immediate but relatively slight fall (25%) in unprotected anal intercourse (UAI). The proportion of men having UAI in the previous year was 61% four years before diagnosis, 72% at diagnosis and 53% one year post-diagnosis – but back to 61% four years after diagnosis.
The San Francisco study, counting the number of partners men had had in the previous three months, presented an apparently very different pattern: ten at diagnosis; declining to seven two years later; 8.5 after five years; then declining again (3.5 ten years after diagnosis).
This study also measured unprotected insertive anal sex (UIAI – most likely to pass on HIV). The number of partners of negative or unknown status with whom men had UIAI declined from 1.8 at baseline to 0.57 after a year and only 0.14 after five years.
The researchers calculated that, without taking viral suppression into account, the San Francisco men reduced the risk of passing on HIV by 71% a year after diagnosis, 87% two years later, and 92% after five years.
CROI 2011
For lots more news from the 18th Conference on Retroviruses and Opportunistic Infections (CROI), visit our CROI webpages at www.aidsmap.com/croi2011.
As well as all our news reports (many of which are linked to the abstracts and webcasts on the official conference website), you can also read the four summary email bulletins we sent from the conference. They are available in English, French, Spanish, Portuguese, Russian and Romanian, to read online or to download and print as PDFs.
- Lalezari J et al. Successful and persistent engraftment of ZFN-M-R5-D autologous CD4 T Cells (SB-728-T) in aviremic HIV-infected subjects on HAART. 18th Conference on Retroviruses and Opportunistic Infections, Boston, abstract 46, 2011.
- Nettles R et al. Pharmacodynamics, safety, and pharmacokinetics of BMS-663068: a potentially first-in-class oral HIV attachment inhibitor. 18th Conference on Retroviruses and Opportunistic Infections, Boston, abstract 49, 2011.
- Grant P et al. Association of Baseline Viral Load, CD4 Count, and Week 4 Virologic Response with Virologic Failure in ACTG Study A5202. 18th Conference on Retroviruses and Opportunistic Infections, Boston, abstract 535, 2011.
- Vallabhaneni S et al. Seroadaptive tactics adopted by HIV-positive MSM can contribute to profound and sustained reductions in HIV transmission risk following HIV diagnosis. 18th Conference on Retroviruses and Opportunistic Infections, Boston, abstract 1038, 2011.
- Heijman RLJ et al. Changes in sexual behaviour after HIV diagnosis among MSM who seroconverted before and after the introduction of ART. 18th Conference on Retroviruses and Opportunistic Infections, Boston, abstract 1034, 2011.