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CROI 2016: Tailored Support Encourages Black Gay Men to Stay on PrEP

Providing culturally tailored counseling and support programs for black men who have sex with men can increase their likelihood of maintaining adherence to pre-exposure prophylaxis (PrEP) for HIV prevention, helping to address a key public health gap in the U.S., according to findings from the HPTN 073 study presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2016)last month in Boston.

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CROI 2016: Removing Clinic Barriers to Rapid ART in Uganda Enables 70% to Start on Same Day

Making point-of-care CD4 T-cell count diagnostics available, revising adherence counseling requirements, and giving extra training to healthcare workers can almost quadruple the number of patients who begin antiretroviral therapy (ART) on the day that they are eligible, Gideon Amanyire of Makerere University reported at the at the Conference on Retroviruses and Opportunistic Infections (CROI 2016)last month in Boston. The package of health system reforms was provided to a typical "real world" group of clinics in Uganda and was embedded in everyday practice, suggesting that the same intervention could have a similar impact elsewhere.

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CROI 2016: Studies Look at Condom Use in IPERGAY French PrEP Trial

An analysis of condom use in the placebo-controlled phase of the French IPERGAY trial of intermittent pre-exposure prophylaxis (PrEP), presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2016) last week in Boston, found that just over half of the participants had high levels of PrEP use but rarely used condoms, and about a quarter were "belt-and-braces" users who had high levels of both PrEP and condom use. However, this left about 1 in 6 trial participants who had low levels of use of both PrEP and condoms. While their condom use did not change, in a minority of this group their PrEP use declined significantly during the study.

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March 10 Is National Women and Girls HIV/AIDS Awareness Day

Thursday, March 10, is National Women and Girls HIV/AIDS Awareness Day (NWGHAAD), an annual opportunity to call attention to the impact of HIV and AIDS on women and girls worldwide. This year's theme is "The Best Defense Is a Good Offense."

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CROI 2016: Early Antiretroviral Therapy Has No Impact on Cardiovascular Disease Marker

Starting treatment at a CD4 cell count above 500 cells/mm3 does not lead to improvement in an important early warning sign of cardiovascular disease, and investigators are still unsure whether people who start treatment at high CD4 counts will have the same increased risk of cardiovascular disease as that reported in people with HIV over the past 15 years, according to findings presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2016) in Boston last week.

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Updated U.S. Guidelines for Antiretroviral Treatment of Children with HIV

The U.S. Department of Health and Human Services has updated its Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. Reflecting recent data from the START and PENPACT1 trials, the guidelines now recommend that all children with HIV start antiretroviral therapy (ART) regardless of CD4 T-cell count, viral load, or clinical symptoms.

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CROI 2016: HIV Home Testing During Pregnancy Doubles Male Partners Who Test

A program of home visits, partner education, and HIV testing for couples in Kenya was able to double the proportion of men who tested during their partner’s pregnancy, Carey Farquhar from the University of Washington reported at the Conference on Retroviruses and Opportunistic Infections (CROI 2016) in Boston last week. Partners became aware of each other’s HIV status without this being linked to an increase in intimate partner violence.

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CROI 2016: Transgender People at High Risk for HIV, But Little Is Known About Prevention and Treatment

Transgender women have among the highest rates of HIV infection, but little is known about HIV prevalence among trans men, Tonia Poteat from Johns Hopkins Bloomberg School of Public Health said in a plenary lecture on transgender health and HIV at the recent Conference on Retroviruses and Opportunistic Infections (CROI 2016)in Boston -- the first ever on this population at CROI. A growing number of studies and prevention and treatment programs are addressing transgender populations, but more research is needed.

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CROI 2016: Modest Kidney Function Decline on Truvada PrEP Supports Need for Monitoring

Participants taking tenofovir/emtricitabine (Truvada) for pre-exposure prophylaxis (PrEP) in 2 major studies experienced modest declines in kidney function that were associated with higher tenofovir drug levels and older age, according to studies presented in a poster discussion session entitled "It’s Complicated: Renal Function and STIs in PrEP Users" at the Conference on Retroviruses and Opportunistic Infections (CROI 2016) last week in Boston. Together, these findings indicate that while Truvada PrEP is safe for most people, ongoing kidney function monitoring is important to promptly catch any problems that may occur.

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Tenofovir (Viread, also in the Atripla, Complera, and Stribild single-tablet regimens) has been used in HIV treatment for more than a decade and is generally considered safe and well-tolerated, but it can cause kidney damage and bone loss in some people.

For this reason, regular kidney function tests are recommended for people taking Truvada for PrEP and those with pre-existing kidney problems are advised not to use it. The U.S. product label for Truvada states that it should not be used for PrEP in people with creatinine clearance below 60 mL/min, and if a decrease is observed providers should "evaluate potential causes and re-assess potential risks and benefits of continued use."

Reports to date from PrEP clinical trials -- which tried to exclude people with pre-existing kidney impairment -- have not revealed notable kidney problems. But sometimes uncommon toxicities only show up after many more people are using a drug.

Renal Function in iPrEx

Monica Gandhi from the University of California at San Francisco presented follow-up findings on kidney function in the pivotal iPrEx trial, the first to show that once-daily Truvada PrEP was highly effective for gay and bisexual men and transgender women who take it consistently. In an open-label extension (iPrEx OLE), in which everyone knew they were taking active Truvada, no one who took the pills at least 4 times a week became infected with HIV.

The iPrEx team looked at the relationship between tenofovir and emtricitabine concentrations in hair samples -- which reflect cumulative drug exposure -- and kidney function over time in iPrEx OLE. Hair samples were collected, serum creatinine (an indicator of kidney function) was measured, and estimated glomerular filtration rate (eGFR, an indicator of creatinine clearance) was calculated every 12 weeks.

Of the more than 1000 iPrEx OLE participants, hair drug levels and creatinine measurements were available for 220 people. A majority of participants in this international study were Latino or mixed race/ethnicity and the median age was 29 years (range 19-70). At baseline the mean creatinine level was 0.89 mg/dL (0.6 to 1.3 is considered normal) and the median estimated eGFR was 112 mL/min (>90 is normal, 60 is a moderate decrease, and <30 is a severe decrease).

While creatinine clearance among participants on Truvada decreased slightly overall -- by an average of 2.5% over 18 months -- there was a consistent and statistically significant relationship between eGFR decline and increasing levels of tenofovir or emtricitabine in hair samples. Among people in the highest quartile of hair drug levels, indicating they took all 7 weekly doses, the eGFR decrease was 5.6%.

Older participants were more likely to see their eGFR fall below 70 mL/min, considered a clinically significant decrease. Among people older than 50 the proportion with eGFR below this threshold rose from 6% in the lowest hair level quartile (indicating about 2 doses a week) to 24% in the highest quartile. Among participants under age 40, however, the proportion never rose above 5% even with daily dosing. People with slightly low eGFR (<90 mL/min) at baseline were also more likely to fall below 70 mL/min, with 27% doing so.

Establishing thresholds of tenofovir/emtricitabine exposure that minimize adverse events while maximizing efficacy "are essential to the real-world roll-out of PrEP," the researchers wrote. 


PrEP Demo Project

Albert Liu from the San Francisco Department of Public Health then presented findings on changes in kidney function among participants in the U.S. Demo Project.

The Demo Project enrolled more than 500 gay and bisexual men and transgender women at risk for HIV at sexually transmitted disease clinics and community health centers in San Francisco, Miami, and Washington, D.C. All received once-daily Truvada PrEP on an open-label basis for a year.

Nearly half of participants were white, about 7% were black, the median age was 35 years (range 18-65), and 12% had hypertension or diabetes. To be eligible participants had to have baseline creatinine clearance of at least 60 mL/min, most had at least 70 mL/min, and the median was 97 mL/min.

In this study tenofovir diphosphate (the metabolized form of the drug in the body) was measured in dried blood spots from a subset
of participants and kidney function was again monitored every 12 weeks. 82% of participants had tenofovir diphosphate levels consistent with taking at least 4 Truvada doses a week.

Overall eGFR declined
by an average of 2.8% from baseline to week 12 -- similar to the finding in iPrEx OLE -- and then remained stable through the end of the study at week 48. Only a small number (11 people or 2.4%) saw their creatinine clearance fall by 10% or more and their serum creatinine rise by 0.2 mg/dL or more on more than 2 occasions; 3 people did have their Truvada suspended due to an elevated creatinine reading, but these were not confirmed with repeat testing and all restarted PrEP with no further interruptions.

Here too, higher tenofovir diphosphate levels in blood spots were associated with significantly greater declines in eGFR. Again, kidney function decline was associated with older age and lower baseline level. Among people with baseline eGFR <90 mL/min, the proportion falling below 70 mL/min ranged from about 6% in the 26-35 age group to about 30% of those older than 45. But among people who started with a eGFR of 90 mL/min or higher, less than 5% fell below 70 mL/min in any age group.

Kidney Damage in Partners PrEP

Finally, Kenneth Mugwanya from the University of Washington in Seattle presented findings on the occurrence of more serious kidney problems among participants in the Partners PrEP trial, which tested once-daily Truvada or tenofovir alone as PrEP for HIV-negative partners in serodiscordant heterosexual couples in Africa.

This study looked at proximal tubulopathy, which occurs when proximal tubule cells in the kidneys are unable to reabsorb substances such as glucose, salts, minerals, and bicarbonate. Sometimes this is subclinical and detected by protein or glucose in the urine, but more serious conditions such as Fanconi syndrome can lead to disruption of the body's pH balance and bone loss. Drugs like tenofovir are excreted by the kidneys and can build up and cause tubule damage, usually in people who have a genetic predisposition or other risk factors. Mugwanya noted that proximal tubulopathy can sometimes occur without an accompanying severe decline in GFR.

This analysis included 776 people randomized to Truvada and 773 randomly assigned to a placebo. Two-thirds were men and the median age was 37 years. Proximal tubulopathy was defined as having any 2 of the following: protein in the urine, glucose in the urine, increased urinary phosphate, or uric acid excretion.

The frequency of proximal tubulopathy was 1.7% (13 people) in the Truvada arm compared with 1.3% (10 people) in the placebo arm, not a statistically significant difference. Protein in the urine alone was seen in 7.3% vs 4.0%, respectively, and this was significant.

A related case-control analysis revealed that 2 of the 52 people (3.8%) who experienced at least a 25% decline in eGFR developed tubulopathy, compared with 3 of 208 people (1.4%) who did not -- again not a significant difference.

There was "no significant association between tubulopathy and clinically relevant decline in eGFR," the researchers concluded, suggesting that "using routine markers of proximal dysfunction will not be an efficient approach to predict the rare events of kidney toxicity in persons using PrEP."

Implications

Taken together, these studies indicate that Truvada is safe and well-tolerated for most people using it for PrEP, but kidney problems -- usually mild or moderate -- may occur in a small proportion of people, especially if they have other risk factors.

"It is often said that these declines are so low it doesn’t matter, but PrEP studies have not monitored people as long as treatment studies," Gandhi said at a CROI press conference. She noted that even minor toxicities can be a concern in a healthy population.

These findings support the Centers for Disease Control and Prevention recommendation that creatinine clearance should be monitored at least every 6 months, with more frequent monitoring and additional tests for people with other kidney safety risk factors such as high blood pressure or diabetes.

Gandhi and Liu agreed that monitoring more often may be appropriate for older people and those who start PrEP with a eGFR <90 mL/min. Conversely, Gandhi also suggested that maybe less frequent monitoring could be considered for people under age 40 with good baseline creatinine clearance.

3/1/16

References

M Gandhi, DV Glidden, AY Liu, et al. Higher Cumulative TFV/FTC Levels in PrEP Associated With Decline in Renal Function. Conference on Retroviruses and Opportunistic Infections. Boston, February 22-25, 2016. Abstract 866.

AY Liu, E Vittinghoff, PL Anderson, et al. Changes in Renal Function Associated With TDF/FTC PrEP Use in the US Demo Project. Conference on Retroviruses and Opportunistic Infections. Boston, February 22-25, 2016. Abstract 867.

KK Mugwanya, JMBaeten, CM Celum, et al. Rare Incidence of Proximal Tubular Dysfunction With Tenofovir-Based Chemoprophylaxis. Conference on Retroviruses and Opportunistic Infections. Boston, February 22-25, 2016. Abstract 868.

CROI 2016: HIV-Related Factors Increase Risk of Stroke

HIV-related risk factors seem to increase the risk of stroke -- the sudden death of brain cells due to a rupture or obstruction of blood vessels in the brain -- according to ongoing research in a growing number of large epidemiological cohort studies. Recent data from 5 of these were presented during the first-ever poster discussion session on stroke at the Conference on Retroviruses and Opportunistic Infections (CROI), which took place last month in Boston.

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CROI 2016: Expanding Treatment and PrEP Could Prevent 185,000 New HIV Infections, CDC Says

Increasing diagnosis, care, and treatment of people living with HIV could lead to a large decrease in HIV incidence, preventing some 168,000 new infections by the year 2020, according to a new Centers for Disease Control and Prevention (CDC) analysis presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2016)last week in Boston. The impact of pre-exposure prophylaxis (PrEP) would be comparatively modest, but its importance would be greater if more HIV-positive people are not on treatment with undetectable viral load.

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CROI 2016: START Study Shows People Starting HIV Treatment Earlier Have Better Quality of Life

Rather than treatment side effects having a negative impact on people’s quality of life when they start HIV treatment, data from the large randomized START study show a modest but statistically significant improvement in quality of life, according to a presentation at the recent Conference on Retroviruses and Opportunistic Infections (CROI 2016) in Boston.

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CROI 2016: Life Expectancy of HIV-Positive People in U.S. Still Lags 13 Years Behind HIV-Negatives

A study presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2016) comparing life expectancies of HIV-positive and HIV-negative people within the Kaiser Permanente health system has found that although life expectancy among HIV-positive people has improved, expected life at age 20 remains 13 years behind that of matched HIV-negative people. This 13-year gap did not improve between 2008 and 2011, the last year of follow-up in this cohort study.

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CROI 2016: High Levels of Chemsex and Slamsex Seen Among HIV+ Men at U.K. HIV Clinics

A survey of HIV-positive clients attending 30 HIV clinics in England and Wales, presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2016)last month in Boston, has found that nearly a third (29%) of gay male patients reported engaging in "chemsex" (defined by the researchers as "the use of drugs to increase disinhibition and arousal") in the past year and that 1 in 10 reported "slamsex" (injecting or being injected with such drugs). Figures were higher for some subgroups: 37% of Londoners reported chemsex and nearly 1 in 5 (19%) of men on antiretroviral therapy (ART) reported slamsex.

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CROI 2016: Study Does Not Support Routine HPV Vaccination to Prevent Anal Cancer in People with HIV

The quadrivalent HPV vaccine Gardasil does not protect older adults with HIV against persistent anal infection with human papillomavirus or the development of high-grade anal lesions (HSIL), but the ACTG A5298 study showed some evidence that it may protect against persistent oral HPV infection, Timothy Wilkin of Weill Cornell Medical College reported at the Conference on Retroviruses and Opportunistic Infections (CROI 2016) last week in Boston.

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FDA Approves Second TAF-Containing Single-Tablet HIV Regimen

The U.S. Food and Drug Administration (FDA) this week approved Gilead Sciences' new once-daily single-tablet regimen Odefsey, containing the NNRTI rilpivirine (developed by Janssen), emtricitabine, and tenofovir alafenamide or TAF, a new formulation that is easier on the kidneys and bones than the older tenofovir disoproxil fumarate or TDF.

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CROI 2016: Option B+ Cuts Mother-to-Child HIV Transmission Dramatically in Malawi

Among women on antiretroviral therapy (ART) prior to pregnancy, early mother-to-child transmission in Malawi’s Option B+ program compares favorably to transmission rates observed in developed countries, Sundeep Gupta told participants at the Conference on Retroviruses and Opportunistic Infections (CROI 2016) last week in Boston.

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CROI 2016: Maraviroc May Work as PrEP in a Combination, but Probably Not Alone

Two studies presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2016) last week in Boston outlined the first findings from the NEXT-PrEP study, otherwise known as HPTN 069. What NEXT-PrEP has discovered so far indicates that the drug maraviroc (Selzentry) could have a role in pre-exposure prophylaxis, or PrEP, when used alongside either tenofovir or emtricitabine (the component drugs in Truvada), but is not potent enough to act as PrEP by itself.

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CROI 2016: Experimental TLR7 Agonist Suppresses HIV-Like Virus in Monkeys After ART Interruption

GS-9620, an investigational toll-like receptor or TLR7 agonist, led to immune activation in a study of macaque monkeys infected with an HIV-like virus, and 2 of the animals treated with multiple doses have maintained viral suppression for at least 3 months after stopping antiretroviral treatment, according to research presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2016) last week in Boston.

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CROI 2016: Injection-Related Indiana HIV Epidemic Is Under Control, But Vigilance Needed

Extensive epidemiological investigation followed by prevention and treatment interventions have largely succeeded in controlling an outbreak of HIV and hepatitis C virus (HCV) infection in rural Indiana linked to injection of prescription opioids, but new cases continue to appear and many other communities may be at risk for similar outbreaks, according to presentations at the Conference on Retroviruses and Opportunistic Infections (CROI 2016) last week in Boston.

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CROI 2016: Long-Acting Cabotegravir PrEP Injection Tolerable and Acceptable, but Dose Adjustment Needed

Attendees at the Conference on Retroviruses and Opportunistic Infections (CROI 2016)last week in Boston heard results from the first Phase 2 (safety, acceptability, and dose-finding) study of a long-lasting injectable formulation of the integrase inhibitor drug cabotegravir for use as pre-exposure prophylaxis (PrEP) in HIV-negative people. The previous day researchers also presented a study of the same injectable drug, plus another injectable, rilpivirine, used as treatment for people with HIV.

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