Wednesday 15 February 2017
Two-drug regimen maintains HIV suppression for 48 weeks after switch
Josep Llibre at CROI 2017. Photo by Liz Highleyman, hivandhepatitis.com
People who switched from standard antiretroviral therapy (ART) to a two-drug regimen of dolutegravir (Tivicay) plus rilpivirine (Edurant) were able to maintain an undetectable viral load up to 48 weeks, according to a late-breaking report at the 2017 Conference on Retroviruses and Opportunistic Infections (CROI) yesterday in Seattle.
“This is the first time we can prove [a two-drug regimen] is non-inferior in a once-daily regimen with no booster, no protease inhibitor and no NRTIs [nucleoside reverse transcriptase inhibitors],” Dr Josep Llibre of University Hospital Germans Trias Barcelona told the conference.
There has been increasing interest in treatment simplification strategies in recent months, especially following last summer’s report of good results for dolutegravir plus lamivudine (Epivir) in a small study of people taking treatment for the first time. ViiV Healthcare’s dolutegravir is a potent integrase inhibitor with a high barrier to resistance, making it a good candidate for simplified therapy.
SWORD-1 and SWORD-2 are identical randomised phase 3 trials recruiting from clinics around the world. Together the studies included 1024 people with HIV who had been on three-drug ART with undetectable viral load for at least a year. Individuals with a history of virological failure, drug resistance or chronic hepatitis B co-infection were excluded.
At baseline the average CD4 cell count was approximately 600 cells/mm3. Their regimens contained integrase inhibitors (20%), NNRTIs (non-nucleoside reverse-transcriptase inhibitors) (54%) and protease inhibitors (26%), as well as two NRTIs.
Participants in these open-label studies were randomly assigned either to switch to the dual regimen (dolutegravir plus rilpivirine) or to stay on their current regimen. The primary endpoint was continued undetectable viral load at 48 weeks, which was achieved by 95% of participants in each arm of the studies.
Virological failure was rare (< 1% in the dual therapy arm and 1% in the unchanged regimen arm). Treatment was generally safe and well tolerated.
The SWORD studies are continuing through to 148 weeks. Also, a new trial will assess a fixed-dose co-formulation of dolutegravir plus rilpivirine. This study will enrol some people with pre-existing drug resistance, to better reflect a ‘real world’ population.
New integrase inhibitor bictegravir matches dolutegravir for first-line HIV treatment
Paul Sax at CROI 2017. Photo by Liz Highleyman, hivandhepatitis.com
Bictegravir, an investigational integrase inhibitor, was highly potent, well tolerated and worked as well as dolutegravir (Tivicay) as part of a three-drug regimen in a phase 2 clinical trial presented to CROI yesterday.
Integrase strand transfer inhibitors – such as dolutegravir – are an increasingly important part of first-line treatment and are recommended in European and US HIV treatment guidelines. Bictegravir (formerly GS-9883) belongs to the same drug class and is manufactured by Gilead Sciences. It can be taken once-daily and does not require a booster such as cobicistat.
The phase 2 study recruited 98 individuals who had not taken antiretroviral therapy (ART) before. They generally had asymptomatic HIV infection with a median CD4 cell count of approximately 450 cells/mm3 and a median viral load of about 4.4 log10 copies/ml.
The 98 participants in this double-blind study were randomly assigned to receive 75mg bictegravir or 50mg dolutegravir, plus 25mg tenofovir alafenamide and 200mg emtricitabine, taken once daily with or without food for 48 weeks.
The primary endpoint was the proportion of people with HIV RNA below 50 copies/ml at 24 weeks, which was achieved for 97% of participants in the bictegravir arm and 94% in the dolutegravir arm. At 48 weeks, an undetectable viral load was maintained for 97% and 91% in the two arms, respectively. Given the small number of participants, these differences were not statistically significant.
No significant drug resistance was detected in either arm. Both regimens were generally safe and well tolerated. As there are concerns about the potential for bictegravir to have a negative impact on kidney function, attention was paid to this. Estimated glomerular filtration rate declines were -7.0 ml/min in the bictegravir arm and -11.3 ml/min in the dolutegravir arm at week 48. There were no discontinuations due to kidney-related adverse events.
These results were promising enough to proceed with four phase 3 trials using a single-tablet regimen of bictegravir, tenofovir alafenamide and emtricitabine. Optimising the formulation allowed for a lower 50mg bictegravir dose in the co-formulation.
Combination HIV prevention drives incidence down in Rakai, Uganda
Mary Grabowski at CROI 2017. Photo by Liz Highleyman, hivandhepatitis.com
The annual rate of new HIV infections (incidence) has fallen dramatically in one of the best-studied groups of people in Africa, the Rakai cohort in southern Uganda. A combination of factors, including wider availability of antiretroviral therapy, increased male circumcision, and later age of sexual debut in young people, all appear to be contributing to this decline.
Data were collected between 1999 and 2016 in 12 surveys from 30 communities in the Rakai Community Cohort. Almost 34,000 people took part in at least one survey.
Rakai is a rural area that has been hard hit by HIV, with around 13% of people living with HIV.
HIV incidence was a steady 1.17% a year over most of the study period, from 2000 to 2010. But after that it started to fall. By 2012 it was 0.8% a year and by 2016 it was 0.66% a year, a 42% decline.
The researchers pointed to three key factors that may explain the reduction:
Incidence fell further in men (by 54%) than in women (by 32%), probably reflecting the benefits men get both from medical male circumcision and from the relatively high rates of treatment coverage in their female partners.
This is the first time a population-level decline in incidence in the Rakai cohort has been seen. The results provide empirical evidence that combination HIV prevention can have a substantial population-level impact, the researchers say.
Infants treated within days of birth may rapidly clear HIV reservoir
Louise Kuhn at CROI 2017. Photo by Liz Highleyman, hivandhepatitis.com
Viral load and viral DNA fall rapidly in infants who begin antiretroviral therapy (ART) within days of birth, two South African studies have found. This shows the potential for clearing the reservoir of HIV-infected cells, but it seems that only a minority of infants may have such a dramatic response to treatment.
Clearing the reservoir of HIV-infected cells is considered to be essential for developing an eventual cure for HIV infection. The reservoir of immune system cells containing HIV DNA is established very soon after infection, so to give the best chance of reducing or clearing HIV DNA in infants, it may be necessary to identify and treat infants within days of birth.
One group of researchers reported on five infants who were treated with ART within eight days of birth. In three infants, HIV RNA declined to less than 100 copies/ml within around three months; in the two remaining infants, HIV RNA fell below 100 copies/ml after six months.
HIV DNA fell very rapidly in the first two weeks of treatment, before entering a more gradual decline throughout the first year of life. HIV DNA was cleared much more quickly than in adults or in infants who began treatment two months after birth.
A second study reported 75 infants, including 30 who started ART within the first two days of life. HIV RNA (viral load) was tested at weeks 1, 2, 4, 8, 12, 16, 20, 24, 32, 40 and 48.
In three infants, HIV RNA ceased to be detectable by qualitative PCR (which would mean an HIV-negative result if this had been used as a diagnostic test). But there was huge variation in viral load responses. Although one-third of infants did achieve undetectable viral load, this took anywhere from 90 to 330 days, and in the remaining infants viral load either rebounded after initial suppression or never fell below the limit of detection.
Point-of-care test for early infant diagnosis improves outcomes
Ilesh Jani at CROI 2017. Photo by Liz Highleyman, hivandhepatitis.com
Using a point-of-care test to diagnose HIV in infants significantly improved retention in care, speeded up antiretroviral therapy (ART) initiation and increased the proportion of infants who started treatment, a large randomised study in Mozambique presented to CROI yesterday found.
HIV diagnosis in infants requires different testing procedures and assays to adults. There are numerous logistical barriers to providing laboratory-based tests for HIV DNA to infants in settings with a high burden of HIV.
Many of these barriers can be overcome if the test is carried out at the health facility while the mother and infant wait, so that treatment can be offered immediately after the result is known. Two point-of-care tests for early infant diagnosis have been approved recently by the World Health Organization. The use of one of them, the Alere HIV-1/2 Detect system, was assessed in a study conducted in Mozambique.
The study randomised 16 health facilities to provide standard-of-care testing or to implement point-of-care testing. Almost 4000 infants were born to women with HIV during the study.
Of the point-of-care results, 99.5% were provided to the infant’s caregiver, compared to 65% of the standard-of-care test results. In the standard-of-care arm, it took a median of 125 days for caregivers to receive the results.
Whereas 90% of infants who tested positive on a point-of-care test had started treatment within two months of diagnosis, only 13% of those tested by the standard method did so. In the point-of-care arm, 62% of infants were still on ART three months after initiation, compared to 43% in the standard-of-care arm.
UNITAID, the international drug and diagnostics purchase fund, is investing US$63 million in point-of-care early infant diagnosis and HIV viral load testing in nine countries in sub-Saharan Africa, in order to test at least 215,000 infants.
Changes in viral suppression over time a better indicator than a single measure
Nicole Crepaz at CROI 2017. Photo by Liz Highleyman, hivandhepatitis.com
Sustained viral suppression over the course of a year may be a better measure than the most recent viral load test result when it comes to understanding access to and engagement in HIV care, according a study by the US Centers for Disease Control and Prevention (CDC). The researchers analysed data from the National HIV Surveillance System for 2014, which includes around 70% of all people aged 13 and over diagnosed with HIV in the US.
They found that 57% had an undetectable viral load on their last test in 2014. But only 48% had an undetectable viral load on all their viral load tests done during the year. Therefore relying on a single viral load test could over-estimate durable viral suppression by 20%.
The CDC also reported that 8% of tested individuals never had an undetectable viral load during 2014. A further 32% of diagnosed individuals did not get tested for viral load during the year, probably indicating that they were not engaged with healthcare and were unlikely to be virally suppressed.
The results revealed some notable demographic disparities. Women, younger people, African Americans and people who inject drugs were less likely to have durable viral suppression.
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