News from ICAAC 2013
The Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2013), held September 10–13 in Denver, brought together nearly 9,000 participants to discuss the latest research in the infectious disease field.
Presentations included an oral session on antiretroviral efficacy, safety and indications, another on HIV and viral coinfections, and more than 100 posters related to HIV, hepatitis B and C, and sexually transmitted infections. Beyond the viral realm, a key theme of the conference was the growing global threat of antibiotic resistance.
HIV Gene Therapy
On the HIV front, Dale Ando from Sangamo BioSciences presented the latest findings from an ongoing study of CCR5 gene therapy (abstract H-1464c). The company’s ZFP Therapeutic technique uses a zinc finger protein to disable the gene for the CCR5 co-receptor, one of the gateways HIV uses to enter T-cells. Normal CD4 cells are collected, modified in the laboratory, and returned to the patient.
The idea was inspired in part by the Berlin Patient, Timothy Brown, who received stem cell transplants to treat leukemia from a bone marrow donor lacking CCR5 due to having two copies of an uncommon natural mutation. Extensive testing has shown that Brown still appears to be HIV-free several years after stopping antiretroviral therapy (ART).
Researchers previously reported that the gene therapy procedure was safe and well tolerated. The modified cells (known as SB-728-T) engrafted, multiplied, and distributed themselves like normal T-cells, and study participants experienced sustained CD4 cell gains lasting up to three years.
But the real test is whether the modified cells are resistant to infection, which can only be determined by interrupting antiretroviral treatment.
Ando reported on seven study participants with one normal and one mutated CCR5 gene. In theory, it should be easier for gene therapy to completely knock out CCR5 co-receptors if nature has already done half the job. All were on ART with fully suppressed viral load.
Participants received a single infusion of 9 billion to 20 billion modified T-cells. CD4 cell levels shot up after the infusion, with one participant approaching 2,500 cells/mm3. Eight weeks later they began a carefully monitored treatment interruption.
Three people were classified as responders, meaning they were able to suppress viral load while off treatment. Three people were non-responders and one was 12 weeks into an ongoing interruption and not yet evaluated.
One responder experienced a rise in viral load after stopping ART, achieved and maintained undetectable HIV for seven weeks, and remains off treatment. Another has had transient undetectable viral load and also remains off ART. The third successfully completed a 20-week treatment interruption and resumed therapy.
All responders had low viral load set-points compared with non-responders (3,600–4,800 vs 50,000–245,000 copies/mL, respectively) and lower HIV DNA levels in resting T-cells (maximum 122 vs 931 copies).
“The data presented today demonstrate that a single infusion of SB-728-T can lead to profound suppression of viral load in the blood and sustained functional control of the virus,” Ando said. “This is the first evidence that sustained functional control of HIV in the absence of antiretroviral therapy is possible.”
Several presentations focused on new antiretroviral drugs, including ViiV Healthcare’s recently approved integrase inhibitor dolutegravir (Tivicay).
Judith Feinberg from the University of Cincinnati reported findings from the FLAMINGO trial comparing 50 mg once-daily dolutegravir vs 800/100 mg once-daily ritonavir-boosted darunavir (Prezista), both with investigator-selected NRTIs (abstract H-1464a).
This study enrolled 484 previously untreated participants. In a “snapshot” analysis at 48 weeks, 90% of people taking dolutegravir and 83% taking darunavir/ritonavir achieved undetectable viral load, with dolutegravir meeting the criteria for statistical superiority. The dolutegravir advantage was especially apparent among people with high pre-treatment viral load: 93% vs 70%, respectively. CD4 cell gains were the same in both arms at 210 cells/mm3.
Dolutegravir’s superiority was driven mostly by fewer early withdrawals and better response among people with high viral load. Both regimens were generally safe and well tolerated, but fewer people discontinued dolutegravir due to adverse events (1% vs 4%).
Previous studies have already shown that dolutegravir works as well as or better than Atripla (efavirenz/tenofovir/emtricitabine) and raltegravir (Isentress). Debbie Hagins presented findings from an analysis of response rates according to sex, race, and age among treatment-experienced participants in the SAILING and VIKING-3 trials (abstract H-1460).
Researchers found that efficacy and tolerability were generally similar across sex, race, and age groups in both studies. However, black participants and people over age 50 had slightly lower response rates.
Paul Sax from Brigham and Women’s Hospital reported on a study comparing Gilead Science’s new tenofovir alafenamide (TAF) formulation against the current tenofovir disoproxil fumarate (TDF or Viread, also in the Truvada, Atripla, Complera, and Stribild combination pills)(abstract H-1464d).
TAF, which is given at a smaller dose than TDF (10 vs 300 mg), reaches a five-fold higher concentration in HIV-infected cells, but the blood plasma level is about 90% lower. Gilead has developed a new single-tablet regimen, similar to Stribild, that substitutes TAF for TDF.
The study showed that the TAF coformulation was just as effective as Stribild, with 88% of people taking both regimens achieving undetectable viral load at 48 weeks. But TAF caused less kidney and bone toxicity.
Estimated GFR, a measure of kidney function, decreased less in the TAF arm than in the TDF arm. Other indicators of kidney function, including protein in the urine and changes in serum creatinine, also favored TAF. Bone mineral density at the spine and hip (measured by DEXA scans) decreased less with TAF than with TDF. Blood biomarkers of bone resorption and formation were also more favorable with TAF.
Long-term kidney impairment and bone loss are concerns as treatment guidelines recommend earlier ART and as Truvada (tenofovir/emtricitabine) is used by more HIV-negative people for pre-exposure prophylaxis, or PrEP.
Gilead researchers conducted a drug utilization analysis to look at “early adopters” of Truvada for HIV prevention (abstract H-663a). The survey collected nationally representative prescription data, stripped of personal identifying information, starting from January 2011; the Food and Drug Administration approved Truvada for PrEP in July 2012.
To get a sense of who is using Truvada for PrEP rather than other indications, the researchers focused on prescriptions for individuals who did not have a diagnosis of current HIV infection, AIDS-related opportunistic illnesses, or hepatitis B (also treated with tenofovir).
Through the first quarter of 2013, they identified 1,774 people prescribed PrEP, accounting for less than 2% of all Truvada prescriptions. Physicians in some 700 cities and towns in 49 states reported prescribing Truvada for PrEP.
Nearly half of people using Truvada PrEP were women and 14% were under age 25. Compared with people taking Truvada for HIV treatment, those taking it for prevention were more likely to be female, young, residing in the south, and under the care of general practitioners rather than infectious disease specialists.
Raltegravir During Pregnancy
Finally, Vincent Jeantils from Jean Verdier Hospital in Bondy, France, reported findings from a study of the safety and efficacy of raltegravir during pregnancy (abstract H-1463).
The analysis included 31 pregnant women at a single center near Paris. Five women started raltegravir before pregnancy and stayed on the drug. The rest began taking raltegravir during pregnancy, three during the second trimester and 23 during the third trimester.
Five women switched to raltegravir due to side effects of their current ART regimen and 19 did so due to poor adherence. In addition, two women tested HIV-positive during late pregnancy and needed to suppress their viral load rapidly before delivery.
Raltegravir was generally safe and well tolerated, with antiviral efficacy similar to that seen in the general population. By the time of delivery most women (81%) had achieved undetectable viral load.
There were 32 live births (including a set of twins) after a median 38 weeks of gestation. No birth defects were observed in any of the babies. Median infant weight was 3,100 g, median height was 48 cm, and median Apgar score was 9.6 out of 10—all within normal ranges. After delivery the infants started on a course of prophylactic antiretrovirals (mostly AZT monotherapy). No adverse events were reported and 93% had undetectable HIV at six months.
The researchers concluded that the safety and efficacy of raltegravir, together with its rapid antiretroviral activity, absence of fetal toxicity in animal studies, and high placental transfer “offers a promising new strategy,” especially if HIV infection is discovered late in pregnancy.
Liz Highleyman is a freelance medical writer and editor-in-chief of HIVandHepatitis.com.