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FDA Approves Gilead's Genvoya Single-tablet Regimen with Tenofovir Alafenamide

The U.S. Food and Drug Administration (FDA) announced on November 5 the approval of Gilead Sciences' Genvoya, a new once-daily single-tablet regimen containing the integrase inhibitor elvitegravir, the booster cobicistat, emtricitabine, and tenofovir alafenamide (TAF) -- a new formulation that is easier on the kidneys and bones than the older tenofovir disoproxil fumarate (TDF).

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EACS 2015: Does Low-level HIV Viral Load Raise the Risk of Disease Progression and Comorbidities?

HIV-positive people with detectable but low viral load -- in the range of 50 to 500 or 1000 copies/mL -- may continue to have a higher risk of AIDS-related events, but their likelihood of experiencing serious non-AIDS events including heart, liver, and kidney disease did not appear to increase, according to a pair of Italian studies presented at the 15th European AIDS Conference last month in Barcelona.

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EACS 2015: When Will Europe Get PrEP?

Pressure is mounting at the community level for access to pre-exposure prophylaxis (PrEP) in Europe and is likely to continue to increase in the absence of decisions by funding authorities and regulators, leading to more informal use, speakers said at the 15th European AIDS Conference this week in Barcelona. At the moment, PrEP is not being funded by national or regional governments in Europe, and any use that is occurring is either the result of individual arrangements with doctors, private prescribing outside the public health systems, or informal and unmonitored use.

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Long-acting Injectable Cabotegravir + Rilpivirine Maintains HIV Suppression for 32 Weeks

A combination of 2 long-acting injectable antiretrovirals -- ViiV Healthcare's experimental integrase inhibitor cabotegravir and Janssen's NNRTI rilpivirine -- given once every 4 or 8 weeks maintained viral suppression as well as a standard oral regimen and appears safe and well-tolerated, the companies announced this week. These findings from the Phase 2b LATTE 2 trial follow earlier reports from the original LATTE study showing that oral cabotegravir plus rilpivirine suppressed HIV as well as an efavirenz-based regimen, but with fewer side effects.

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IAPAC Summit: How Do We Treat the World? Experts Discuss Moving to Universal HIV Treatment

What practical steps does the global healthcare community need to take in order to expand HIV treatment so that it can reach everyone who is diagnosed? And how do we expand testing so that as many HIV-positive people as possible are diagnosed, on treatment, and virally suppressed? These were the themes of the discussion concerning what used to be called "Treatment as Prevention" at the recent 2015 IAPAC Controlling the HIV Epidemic with Antiretrovirals summit in Paris.

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EACS 2015: London Clinic Survey Shows Impact of Chemsex on Condom and PEP Use

A survey of gay men in London using drugs during sex -- known as "chemsex" --has shown high levels of unprotected sex and hepatitis C among both HIV-positive and HIV-negative men, high levels of post-exposure prophylaxis (PEP) use, and a high frequency of injection drug use, according to research presented at the 15th European AIDS Conference last month in Barcelona.

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EACS 2015: TAF Single-Tablet Regimen Shows Good Efficacy, Improved Kidney and Bone Safety

A single-tablet regimen containing the new tenofovir alafenamide (TAF) -- to be marketed as Genvoya -- suppressed HIV as well as a coformulation containing the older tenofovir disoproxil fumarate (TDF), according to a poster presented this week at the 15th European AIDS Conference in Barcelona. A related studyfound that people who switched from an atazanavir (Reyataz)-based regimen to the new combo had superior virological outcomes, and in both clinical trialsparticipants saw improvements in kidney and bone biomarkers.

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EACS 2015: Majority of Migrants with HIV in Europe May Have Acquired Virus in New Country

A study presented at the 15th European AIDS Conference last month in Barcelona found evidence that the majority of migrants living with HIV in Europe, and who were diagnosed less than 5 years ago, probably acquired the virus in their host country rather than the one in which they were born. The aMASE (Advancing Migrant Access to Health Services in Europe) study found that the proportion of people with a documented or probable date of HIV infection later than their move to, or within, Europe was higher than those with a documented or probable pre-migration infection date, and that this applied to all risk groups, all areas of origin, and both sexes.

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EACS 2015: Can Dolutegravir Dual Therapy or Monotherapy Keep HIV Suppressed?

The potent integrase inhibitor dolutegravir taken with a single well-tolerated NRTI was able to fully suppress viral load in people initiating antiretroviral treatment for the first time, while dolutegravir alone was able to keep HIV suppressed in most treatment-experienced people who started with undetectable viral load, according to a set of studies presented at the 15th European AIDS Conference this week in Barcelona. After these presentations experts offered evidence in favor of and opposed to simplifying treatment by reducing drug burden, disagreeing about whether this strategy is beneficial or too risky.

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European Medicines Agency Drops Class-wide Nucleoside/Nucleotide Drug Warning

The European Medicines Agency recently updated its advice about lipodystrophy and lactic acidosis for people being treated for HIV, and called for modification of the warning required on all nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), as these toxicities are now known to be associated with specific drugs that are no longer widely used in high-income countries. U.S. advocates have asked the Food and Drug Administration (FDA) to make a similar change.

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EACS 2015: Benefits of Early HIV Treatment Are Clear, But Issues Raised by START and D:A:D Still Unresolved

The long-running controversy over when to start antiretroviral therapy (ART) has been definitively answered, but research is still needed to fully understand the implications of the large START and D:A:D studies, Professor Jens Lundgren from the University of Copenhagen said at a joint plenary session of the 15th European AIDS Conference and the 17th International Workshop on Co-morbidities and Adverse Drug Reactions in HIV.

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EACS 2015: Risk of Heart Attack Rises with Length of HIV Infection, Regardless of Age

A decade after becoming infected, a person living with HIV has approximately twice the risk of heart attack compared to someone who has just acquired HIV, regardless of the age at which they seroconverted and after taking into account the effects of aging, according to an analysis of 18,468 people with HIV presented at the 15th European AIDS Conference in Barcelona last week. Stopping smoking, improving diet, and exercising are especially important for people living with HIV long-term, the researchers suggested.

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EACS 2015: Modest Bone Loss Seen in Young Men Taking Truvada for Pre-Exposure Prophylaxis

Young men participating in a pre-exposure prophylaxis (PrEP) demonstration project experienced modest but significant bone loss after starting Truvada, according to findings presented today at a joint session of the 15th European AIDS Conference and the 17th International Workshop on Co-morbidities and Adverse Drug Reactions in HIV.

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Presenter Kathleen Mulligan from the University of California at San Francisco reported that bone mineral density (BMD) declines were seen in men who had tenofovir blood levels shown to be highly protective against HIV infection; in contrast, bone density increased in men with undetectable drug levels, as expected for young men of their age.

Tenofovir disoproxil fumarate (Viread, also in several single-tablet regimens) is one of the most widely used antiretrovirals, and the Truvada(tenofovir/emtricitabine) coformulation is increasingly used for HIV prevention. The iPrEx study showed that daily Truvada reduced the risk of HIV infection by 92% among gay men with measurable blood drug levels.

Tenofovir is considered to be generally safe and well-tolerated, but it is known to cause a small amount of bone loss soon after starting therapy. Bone loss has been seen in HIV-positive adults taking tenofovir-containing antiretroviral therapy and in infants exposed to tenofovir during gestation. Tenofovir-related bone loss has not yet been studied extensively in HIV-negative people, or in adolescents and young adults -- the age at which peak bone density occurs.

This analysis looked at bone density changes among participants in ATN 110, an open-label demonstration project investigating the safety and feasibility of PrEP for young gay men age 18-22 years. Results of the main study were presented at the International AIDS Society Conference this summer.

Bone mass generally peaks during early adulthood -- typically around age 20 -- after which it begins to gradually decline. Peak bone mass is an important predictor of fracture risk later in life, Mulligan noted as background.

ATN 110 enrolled 200 at-risk HIV-negative young men who have sex with men in 12 U.S. cities. The median age was 20 years, nearly half were African American, and about a quarter were Latino. Overall body weight was normal, but with a wide variation (median body mass index 23.6; range 17.3-58.9 kg/m2).

All participants were offered PrEP using once-daily Truvada for 48 weeks, along with a full package of HIV prevention services including risk reduction and adherence counseling, testing and treatment for sexually transmitted infections, and free condoms. Drug levels were measured throughout the study and dosing frequency was estimated based on tenofovir concentrations in dried blood spots.

The bone sub-study performed dual X-ray absorptiometry (DXA) scans of the hip, spine, and whole body at baseline and at weeks 24 and 48. The 4 participants who became HIV-positive during the study were excluded from the bone analysis.

Bone mineral density levels were lower than expected at baseline, falling below norms for age and race/ethnicity; 8.1% of participants had spine BMD, 6.1% had hip BMD, and 3.7% had whole body BMD below standard international thresholds for low bone mass. Mulligan noted that low bone mass has previously been reported in other studies of at-risk HIV-negative men.

At week 24 after starting Truvada, bone density decreased at the spine (by about -0.2%), hip (by about -0.4%) and whole body (by about -0.8%), with the latter 2 changes being statistically significant. At 48 weeks, hip BMD continued to decrease steeply (falling by about -1.0%) and whole body BMD further decreased by a small amount, but spine BMD started to increase and in fact rose above the baseline level.

Z-scores -- a measure of deviation from the norm for people of the same age and race/ethnicity -- decreased for the spine, hip, and whole body at both week 24 and week 48; all these changes were significant.

The researchers then looked at the relationship between bone loss and tenofovir concentrations in dried blood spots. More than half of participants had drug levels shown to confer a high level of protection -- indicating that Truvada was taken at least 4 times per week -- for the first 12 weeks. Adherence declined over time, however, and by week 48 only about a third of participants still had highly protective drug levels.

This allowed the researchers to compare bone density changes between men who had highly protective tenofovir levels and those with lower levels, showing that bone loss at the spine and hip through week 48 was correlated with tenofovir exposure.

Men with highly protective tenofovir levels showed spine bone loss of about -0.5% at week 24 and about -1.5% at week 48, while those with undetectable drug levels saw their bone density rise by approximately the same amount. Hip bone density decreased by smaller amounts at weeks 24 and 48 in men with protective drug levels, while remaining unchanged in those with undetectable drug levels.

Mulligan noted that differences in bone loss between men who took Truvada 7 days a week and those who took it 4 times a week were not significant, so it is not clear whether taking PrEP less often -- perhaps using an intermittent or "on demand" dosing schedule like the one used in the Ipergay study -- would be protective against bone loss.

Looking at bone fractures, about a quarter of participants reported that they had sustained fractures prior to the study. During the study period 5 participants experienced 8 fractures, all due to trauma (slamming fingers in a door, a vehicle accident, a fall, and a fight). None of the men with fractures had Z-scores indicating low bone mass.

"Although the BMD losses were generally modest, their occurrence before attainment of peak bone mass in young men who already have low bone mass may increase their risk of fragility in adulthood," the researchers concluded.

In response to an audience question, Mulligan said there was "very little evidence" of kidney toxicity among PrEP recipients, with very few cases of protein or glucose in the urine and little change in serum creatinine.

The study will continue to follow participants for a year to determine whether bone loss is reversible after stopping Truvada.

10/21/15

Reference

K Mulligan, B Rutledge, BG Kapogiannis, et al. Bone Changes in Young Men Ages 18-22 Enrolled in a Pre-Exposure Prophylaxis (PrEP) Safety and Demonstration Study Using Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC). 15th European AIDS Conference and 17th International Workshop on Co-morbidities and Adverse Drug Reactions in HIV. Barcelona, October 21-24, 2015.

Coverage of the 15th European AIDS Conference

HIVandHepatitis.com coverage of the 15th European AIDS Conference, sponsored by the European AIDS Clinical Society (EACS), October 21-14, 2015, in Barcelona.

Conference highlights include antiretroviral therapy and treatment strategies, new European HIV treatment guidelines, HIV pre-exposure prophylaxis (PrEP), and treatment for hepatitis C.

Full listing by topic

15th European AIDS Conference website

10/28/15

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EACS 2015: Can Europe Reach the 90-90-90 Target for HIV Treatment by 2020?

The European region needs to step up prevention and treatment activities if it is to reach the UNAIDS target of 90% of people with HIV diagnosed, 90% of those diagnosed on treatment, and 90% of those on treatment with fully suppressed viral load by 2020, the United Nations Secretary-Generals Special Envoy on HIV/AIDS in Eastern Europe and Central Asia told the opening session of the 15th European AIDS Conference today in Barcelona on Wednesday.

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[Produced in collaboration with Aidsmap.com]

The 90-90-90 target promoted by UNAIDS, if achieved, would result in 73% of people living with HIV having undetectable viral load. Mathematical modeling suggests that achieving this target by 2020 would end the AIDS epidemic by 2030.

"Europe is not done with AIDS and there is no room for complacency," Professor Michel Kazatchkine told delegates.

"There isn’t one Europe," Kazatchkine said at a press conference on the opening day of the conference. The World Health Organization's Europe region covers 53 countries, and "in fact, there are 3 Europes -- Eastern Europe, Central Europe, and Western Europe -- with different epidemics, different responses, and different levels of success."

The Eastern European epidemic continues to grow, driven largely by unchecked epidemics among people who inject drugs, but autonomous epidemics are also emerging among heterosexual men and women through sexual transmission in the region, Kazatchkine warned. These high levels of transmission make it unlikely that Eastern Europe will be in a position to reach the 90-90-90 target by 2020, he said. Prevention services are not accessible at sufficient scale, access to harm reduction remains very limited, and very low levels of cooperation on the part of government towards non-governmental organizations impedes the scale-up of prevention activities.

In Central Europe, despite low prevalence, HIV incidence has been rising gradually in many countries. The epidemic remains highly concentrated among men who have sex with men and people who inject drugs, but there is "limited willingness to pay" for programs aimed at these vulnerable groups among governments in the region, Kazatchkine said. He reminded delegates of the consequences of reducing HIV prevention services in the region: after Global Fund funding for harm reduction was gradually withdrawn from Romania when it joined the European Union in 2007, the country suddenly went from a minimal epidemic to high incidence among people who inject drugs in less than 2 years.

Although Western Europe appears to have everything needed to mount a successful response to HIV, the overall level of new infections has remained stable over the past decade. Despite universal health coverage, excellent HIV care, and high levels of social support, new infections have increased among men who have sex with men over the past 10-15 years. Much more intense efforts are needed in both prevention and treatment, but the 90-90-90 targets should be achievable for both Western and Central Europe, Kazatchkine predicted.

But, he told the conference, "If we do not intensify our efforts in the next 5 years, we will not be on the path to ending AIDS."

"We need to look carefully at the weaknesses in the European response. We are still missing many infections among men who have sex with men and migrants from countries with generalized epidemics," Kazatchkine said. In particular he expressed concern about testing frequency among men who have sex with men: if a large proportion of new infections among men who have sex with men are a consequence of acquiring HIV from partners who are themselves recently infected, yearly testing may be too infrequent to pick up recent infections and start treatment early enough to interrupt a chain of new infections. "Self-testing will be one of the solutions," he suggested.

A focus on the groups of people left behind will also be necessary: people who inject drugs, migrants, sex workers, and men who have sex with men continue to lack access to testing, treatment, and care in many settings in the region, yet are the groups most affected by HIV.

Closing the treatment gap will be necessary in order to reach the 90-90-90 target, Kazatchkine said. At the moment, the number of new HIV diagnoses in many countries in Eastern Europe continues to exceed the number of people who start treatment each year, which means that the treatment gap is growing, not shrinking. The treatment gap is made worse by national guidelines restricting treatment to people with CD4 cell counts below 350 cells/mm3 throughout Eastern Europe and Central Asia, and by alarmingly poor rates of diagnosis and retention in care. The average treatment cascade for the region as a whole shows that only 47% of people living with HIV know that they are infected. In the Russian Federation, the country with the largest number of people living with HIV, only 12% of HIV-positive people are on treatment.

Late diagnosis continues to be a major challenge for achieving high treatment coverage in Western Europe, especially among migrants who often lack good access to health care. In Eastern Europe, treatment coverage is around 35%, compared to a global average approaching 60%, Kazatchkine told the press conference. "People are very reluctant to go to services because of stigma and discrimination, because of a lack of coordination between TB and HIV services, and because of criminalization of people who inject drugs." Less than 10% of people who inject drugs who are living with HIV are currently accessing treatment in Eastern Europe, he said.

Tamás Berezcky of the European AIDS Treatment Group said that stigma and discrimination are the biggest barriers to testing and treatment among men who have sex with men in Central Europe, and stigma within the community is an important barrier to seeking care. "If you look at how men who have sex with men treat other MSM with HIV it’s very depressing," he told the press conference. He said that stigma is being reinforced by a lack of information about HIV, including a lack of awareness regarding recent advances in HIV treatment, the normal life expectancy of people who receive appropriate antiretroviral therapy, and the impact of treatment on transmission.

There is also insufficient focus on partnership with community organizations, Kazatchkine said. Berezcky called on scientists to join in partnership with the community to achieve implementation.

The financial sustainability of the HIV response in Eastern and Central Europe is also a serious concern following the withdrawal of Global Fund support for HIV and tuberculosis programs in the region. Global Fund support has come to an end as a result of a decision to focus future funding on lower-income countries, despite the political difficulties of funding the necessary prevention and treatment services in Eastern Europe.

10/21/15

Source

15th European AIDS Conference. Barcelona, October 21-24, 2015.

EACS 2015: START Substudies Show More Bone Loss with Early ART, But No Differences in Lung or Neurocognitive Function

Participants who started antiretroviral therapy (ART) soon after HIV diagnosis in the large START trial showed a greater decrease in bone density at the hip and spine compared to those who deferred treatment, researchers reported at a joint session of the 15th European AIDS Conference and the 17th International Workshop on Co-morbidities and Adverse Drug Reactions in HIVlast week in Barcelona. There was no significant difference in the likelihood of fractures, however, and 2 other START substudies saw no differences in lung function or neuropsychological performance between people randomized to immediate or deferred ART.

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Starting antiretroviral treatment before development of serious immune system damage greatly reduces the risk of HIV disease progression and death, but early treatment can potentially also have drawbacks including longer exposure to toxic drugs. The INSIGHT START (Strategic Timing of Antiretroviral Treatment)trial was designed to address the long-standing controversy over the optimal timing of HIV treatment, especially for people who still have high CD4 counts.

Briefly, START enrolled 4685 HIV-positive adults in 35 countries who entered the trial with a CD4 count above 500 cells/mm3. They were randomly assigned to either start treatment at study entry or delay therapy until their CD4 count fell below 350 cells/mm3 or they developed AIDS-related symptoms.

Overall, nearly three-quarters were men and the group was quite young (average age 36 years). They had good immune function at baseline, with a median CD4 count of 651 cells/mm3. Over the course of follow-up, the CD4 count of people in the deferred group was 194 cells/mm3 lower, on average, than that of the immediate group.

The START Data Safety and Monitoring Board stopped the randomized portion of the trial ahead of schedule in May 2015 after it determined that there was already enough evidence to show a benefit of immediate treatment. At that point, the average follow-up time was 3 years.

The primary START results, presented this summer at the International AIDS Society Conference in Vancouver and published in the August 27 New England Journal of Medicine, showed thatparticipants randomized to start ART soon after HIV diagnosis had a significantly lower risk of illness and death than those who waited. The immediate treatment group not only had a 72% lower risk of AIDS-related infections and malignancies compared to the deferred group, but also were 39% less likely to experience serious non-AIDS events (heart, liver, and kidney events and non-AIDS cancers) or death.

The START design included several substudies looking at the effects of early versus deferred therapy on specific outcomes known or suspected to be associated with HIV infection or its treatment, including bone density, lung function, and neurocognitive function.

Bone Density Substudy

Jennifer Hoy from Monash University and the Alfred Hospital in Melbourne presented findings from the START bone mineral density (BMD) substudy. This analysis included 193 people randomized to the early ART group and 204 in the deferred ART group.

Substudy participants underwent dual X-ray absorptiometry (DXA) scans of the lumbar spine, total hip, and femoral neck at baseline and annually thereafter. The researchers looked atZ-scores, a measure of deviation from BMD norms for people of the same age, sex, and race, as well as T-scores, based on the norm for young white women.

Participants were followed at 33 study sites and 16 radiology centers in Brazil and Peru (38%), India and Thailand (30%), South Africa (11%), Europe (9%), Australia (8%), and the U.S. (4%). This distribution differed from the START study as a whole, which had more than 200 sites, with 33% in Europe and just 8% in Asia. As in the full population, 26% were men, but the substudy participants were a bit younger (32 vs 36 years), more likely to be Asian (32% vs 8%) or Latino (24% vs 14%), and less likely to be black (19% vs 30%) or white (20% vs 45%); this is relevant because racial/ethnic groups have different bone density norms.

Looking at known or potential risk factors for low bone density, 19% were current smokers, 4% were heavy drinkers, 12% reported recreational drug use, 4% had hepatitis C virus (HCV) coinfection, and 13% of the women were menopausal. Body weight and kidney function were normal (median BMI 24; median eGFR 114 mL/min). Baseline Z-scores were below the norm (-0.3 for the hip; -0.8 for the spine). More than a third (38%) met the criteria for low BMD, 3% had osteoporosis, and 8% reported previous fractures.

People in the immediate arm were on any antiretrovirals for 95% of the total follow-up time, compared with 18% in the deferred arm; they were exposed to tenofovir disoproxil fumarate (Viread, also in Atripla and other single-tablet regimens) for 79% and 15% of follow-up time, respectively. Protease inhibitor use was uncommon (19% and 3% of follow-up time).

Results

  • Over a mean follow-up period of 2.2 years, total spine BMD decreased in the immediate ART arm during the first year (by about 2.0%) and then stabilized, while remaining about the same in the deferred arm (less than -0.5% decline).
  • Total hip BMD continued to decline over 3 years in both arms, but the percentage loss was greater in the immediate compared to the deferred group (about -2.0% vs -0.5% at 12 months and -3.5% vs -2.0% at 36 months).
  • These differences were statistically significant for spine BMD at 12, 24, and 36 months, and for hip BMD at 12 and 24 months (only about 30% of participants had the third year DXA).
  • Overall estimated mean differences were -1.6% for spine BMD and -1.5% for hip BMD -- that is, 1.6% and 1.5% lower in the immediate group -- both of which were significant.
  • Comparing people who were actually on or off ART (rather than group assignment), the mean differences were larger: -2.2 for spine BMD and -2.1% for hip BMD, again both significant.
  • Having a lower CD4 count was associated with greater bone loss at the spine, while longer time since HIV diagnosis was the major factor affecting hip bone loss; however, the only significant risk factor in an adjusted analysis was using a protease inhibitor in the first ART regimen.
  • 7 people in the immediate ART group and 4 in the deferred group (1.72 and 0.90 per 100 person-years [PY]) were diagnosed with osteoporosis, giving a hazard ratio of 2.0 or twice the risk, but the difference was not significant.
  • In the main START study (not just the substudy), 57 people in the immediate arm and 50 in the deferred arm sustained fractures (0.71 and 0.81 per 100 PY), a hazard ratio of 1.16 that again was not significant.
  • Minimal trauma fractures -- those that occur due to bone fragility rather than traumatic injury -- were actually less common in the immediate ART group (0.18 vs 0.32 per 100 PY; hazard ratio 0.57), but this also was not significant.

In summary, this analysis showed "significantly greater loss of BMD at both the hip and spine in those randomized to immediate ART," the researchers concluded, but there was "no evidence of difference in development of osteoporosis between groups (or fractures in the main START study)."

START Pulmonary Substudy 


Ken Kunisaki from the University of Minnesota presented results from the START pulmonary substudy, which compared changes in lung function in the immediate and deferred ART groups.

Chronic obstructive pulmonary disease (COPD) is an emerging HIV comorbidity, Kunisaki noted as background. Observational studies have shown that people with HIV are at higher risk for COPD, but there is conflicting evidence about whether ART is associated with elevated risk. The underlying mechanisms are unclear, but could be related to inflammation, increased risk of pneumonia and other lung infections, changes in lung microbiota, and perhaps antiretrovirals themselves, he said.

In this substudy participants had spirometry tests done at baseline and annually thereafter. Spirometry is used to assess lung function by measuring the amount of air inhaled and exhaled. The primary measure in this analysis was the change in forced expiratory volume, or the amount of air a person can blow out in 1 second (FEV1). FEV1 typically peaks around age 25 and then declines over time; a level below 30% of the maximum is disabling. Results were stratified by smoking status.

This substudy included 518 people randomized to the early ART group and 508 in deferred ART group. Again, the distribution differed from the study as a whole, with about 30% each in Africa and Europe, 19% in South America, and about 10% each in Asia and the U.S. About 70% were men and the median age was 36 years. About 60% had never smoked, 28% were current smokers, and 11% were former smokers.

Results

  • Over a median follow-up time of 2.0 years, FEV1 slope showed "absolutely no difference" between the immediate and deferred ART arms for either smokers or non-smokers, Kunisaki reported.
  • Among smokers, FEV1 fell by -34 mL/year in the immediate ART group and by -31 mL/year in the deferred group, a difference that was not statistically significant.
  • There was also no significant difference between treatment arms among non-smokers, -29 vs -22 mL/year, respectively -- though the smokers did see larger declines than non-smokers in both arms.
  • Turning to self-reported lung function using the standardized St George’s Respiratory Questionnaire for COPD (SGRQ-C), scores fell by -1.1 in the immediate ART arm and by -0.5 in the deferred arm among smokers, and fell by -1.1 while rising by +0.4 among non-smokers; neither difference was significant.
  • Looking at specific domains for symptoms, activity, and impact, the only significant difference was worsening symptoms reported by smokers in the immediate ART group (-2.9 vs +1.6).

Though changes were small and mostly not significant, it is notable that among non-smokers scores for all 3 domains and the overall SGRCQ-C fell in the immediate ART arm -- indicating improvement -- while rising in the deferred arm.

"Immediate vs deferred ART has no impact on lung function decline" in HIV-positive people with CD4 counts above 500 cells/mm3, the researchers concluded. "Immediate ART can be offered without concern for increasing COPD risk in these patients."

Neurology Substudy

Finally, Richard Price from the University of California at San Francisco presented findings on behalf of the START neurology substudy, which looked at changes in performance among 592 participants randomized to early or deferred ART.

Participants in this substudy completed neuropsychological tests measuring various aspects of neurological function at baseline, at months 4, 8, and 12, and then annually. The researchers compared mean changes in QNPZ-8 scores, an average score encompassing 8 tests of fine motor control, processing speed, verbal learning, verbal memory, and "executive" function, or overall management of cognitive function.

Participants in this substudy came from South America (42%), Europe (25%), Thailand (15%), the U.S. (14%), and Australia (4%). Two-thirds were men and the median age was 34 years. About 8% had a prior psychiatric diagnosis and 5% reported alcoholism or drug dependence. They were described as a "high functioning" group, with 76% being employed and 80% having had either vocational training or college/university education; this is relevant because past research has shown a link between neurocognitive performance and education level.

Results

  • Over 2 years of follow-up, QNPZ-8 scores rose in parallel from baseline, increasing by similar amounts in the immediate and deferred ART groups; Price noted that this likely reflects a "practice effect" seen when people repeatedly take the tests.
  • The estimated difference between the groups was -0.01, which was not statistically significant.
  • By month 60, scores in the immediate arm rose more steeply while those in the deferred group declined, but there were only a small number of participants still being followed at that point and Price said this divergence "shouldn’t be paid attention to."

This study showed "no overall neurocognitive advantage (or disadvantage) for immediate ART initiation in asymptomatic treatment-naive individuals with high CD4 counts," the researchers concluded. These findings suggest that there is both a "low incidence of ART-preventable neurocognitive impairment" in this population and a low incidence of neurocognitive decline while off treatment, as well as "no clear evidence of neurotoxicity."

In response to a question Price said that use of efavirenz (Sustiva) -- an antiretroviral known to cause central nervous system side effects -- was very common. No obvious effects of efavirenz were noted, but this is being analyzed further.

Interpretation

Taken together, these studies offer reassurance that early ART does not lead to serious or clinically significant adverse outcomes, though the greater bone loss in the immediate arm is cause for concern. On the other hand, the substudies also did not reveal major advantages for immediate ART with regard to bone, lung, or neurological outcomes.

A limitation of all these substudies is that START enrolled a relatively young population with recent HIV diagnosis and good immune function. Observational studies that have seen higher rates of cardiovascular, neurological, and other conditions among people with HIV have generally looked at older groups of patients, and problems may increase in this group as they age.

Also, as noted, the randomized portion of START was stopped early, so the average 3 years of follow-up was shorter than expected. Researchers are continuing to follow participants to look at longer-term outcomes, and cardiovascular and liver substudies are also underway. But now that both arms have been advised to start treatment, the differences between them are likely to diminish over time.

10/27/15

References

J Hoy, B Grund, M Roediger, et al (INSIGHT START Bone Mineral Density Substudy Group). Effects of Immediate Versus Deferred Initiation of Antiretroviral Therapy on Bone Mineral Density: A Substudy of the INSIGHT Strategic Timing of Antiretroviral Therapy (START) Study. 15th European AIDS Conference and 17th International Workshop on Co-morbidities and Adverse Drug Reactions in HIV. Barcelona, October 21-24, 2015. Abstract ADRLH-62.

KM Kunisaki, DE Niewoehner, G Collins, et al (INSIGHT START Pulmonary Substudy Group. Lung Function Decline in HIV: Effects of Immediate versus Deferred ART Treatment on Lung Function Decline in a Multi-site, International, Randomized Controlled Trial. 15th European AIDS Conference and 17th International Workshop on Co-morbidities and Adverse Drug Reactions in HIV. Barcelona, October 21-24, 2015. Abstract PS1/1.

E Wright, B Grund, K Robertson, R Price (INSIGHT START Neurology Substudy Group). No Difference between the Effects of Immediate versus Deferred ART on Neuropsychological Test Performance in HIV-positive Adults with CD4+ Cell Counts above 500 cells/μL: The Strategic Timing of Anti Retroviral Treatment (START) Neurology Substudy. 15th European AIDS Conference. Barcelona, October 21-24, 2015. Abstract PS10/6.

IDWeek 2015: Post-Treatment Control of HIV Appears Rare, Biomarkers May Help Predict Rebound

Only 4 individuals out of nearly 5000 people receiving care at U.S. military health facilities were found to exhibit immune control of HIV after starting antiretroviral therapy (ART), achieving viral suppression, and interrupting treatment, according to a presentation at IDWeek 2015 this month in San Diego. A recently published related study identified several biomarkers that may help predict who will be post-treatment controllers, a useful tool for HIV cure research.

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EACS 2015: HIV Maturation Inhibitor BMS-955176 Shows Good Safety and Efficacy in Phase 2a Trial

Bristol-Myers Squibb's next-generation maturation inhibitor BMS-955176 demonstrated good antiviral activity against HIV subtypes B and C in a short proof-of-concept study, and appeared to be safe and well-tolerated, according to findings presented last week at the 15th European AIDS Conference in Barcelona.

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PrEP Preferences of Gay Men Are Predicted by Frequency and Predictability of Sex

A survey from the U.S. and Canada recently published in the Journal of Acquired Immune Deficiency Syndromes reveals that, on the whole, HIV-negative gay men would rather take pre-exposure prophylaxis (PrEP) intermittently and only before they anticipate sex, in what has been called "event-driven" or "on-demand" PrEP.

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EACS 2015: With EACS Release, All International HIV Treatment Guidelines Agree on When to Start

The new European AIDS Clinical Society (EACS) Guidelines, released last week at the15th European AIDS Conference in Barcelona, bring Europe into line with the rest of the world by recommending HIV treatment upon diagnosis for all patients. This is the first time since 2006 that all international guidelines have agreed on their "when to start" recommendations.

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IDWeek 2015: Many People with HIV Are Not Virally Suppressed on Antiretroviral Therapy

A third of people with HIV on antiretroviral therapy (ART) do not have sustained viral suppression and many are not receiving regimens recommended by the latest U.S. treatment guidelines, according to data from the Medical Monitoring Project presented at IDWeek 2015 last week in San Diego. However, this study included many people with long-term HIV infection who may not have been able to use preferred first-line regimens.

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