The FDA on Monday approved the latest combo HIV combo therapy from Gilead Sciences: Descovy.
Story via Fortune
The therapy improves upon existing Gilead HIV medicine: Viread, according to the company, because it contains a newer formulation of a key ingredient called tenofovir. That will allow Descovy to be delivered to patients at lower doses, potentially foretelling fewer negative side effects.
Gilead spokespeople described the therapy as “the first new HIV treatment backbone” approved in more than a decade. “Descovy represents an important evolution in HIV care,” said Chief Scientific Officer Norbert Bischofberger. “As part of a single tablet regimen or partnered with a third agent, the components of Descovy offer patients a simple and effective combination with a safety profile that has the potential to improve health.”
The California-based drugmaker has racked up a series of new HIV approvals in recent months, including Genvoya and Odefsey.
But some of these have been met with patient advocate criticism. Last autumn, the AIDS Healthcare Foundation alleged that Genvoya’s approval amounted to an attempt by Gilead to evergreen its patents on the older HIV med Stribilid, since the two drugs are essentially identical other than Genvoya’s newer tenofovir formulation.
Between HIV/AIDS therapies and Gilead’s hepatitis C treatments Sovaldi and Harvoni, the firm’s antiviral franchise brought in more than $30 billion in global 2015 sales.
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Adherence makes all the difference to the efficacy of pre-exposure prophylaxis (PrEP), the 19th Conference on Retroviruses and Opportunistic Infections (CROI) heard on Tuesday.
Further data were presented from two trials of PrEP (giving anti-HIV drugs to HIV-negative people to prevent infection), which announced dramatically different results last year.
In April 2011, the FEM-PrEP study found that giving HIV-negative women tenofovir/FTC (Truvada) pills to prevent their acquiring HIV was totally ineffective: there was no difference in HIV incidence between women taking Truvada and women taking placebo.
In July 2011, however, the Partners PrEP study found that Truvada was 73% effective in preventing HIV transmission between heterosexual partners of different HIV status.
How do we explain why giving HIV-negative women antiretroviral pills made no difference to the HIV infection rate in one trial, but prevented at least two in every three infections in the other? The difference, it appears, is that in the Partners PrEP trial, adherence to the study medication was very high, whereas in FEM-PrEP, despite counselling and support, less than half the women took their PrEP pills regularly.
The Partners PrEP study
The Partners PrEP study enrolled 4758 serodiscordant couples in Kenya and Uganda; the HIV-negative partner was female in 38% of couples. This study had three arms: a daily tenofovir pill, a daily Truvada pill, or placebo.
There were 17 infections in participants on tenofovir, 13 on Truvada and 52 on placebo. Efficacy overall was 75% in those assigned Truvada and 67% in those assigned tenofovir, though confidence intervals (44% to 81% in tenofovir and 55% to 87% for Truvada) overlapped, so the efficacy of the two regimens was the same statistically. The same was true of efficacy observed in women (65%) and men (70.5%).
Adherence according to pill counts of unused medication was 97%. A substudy (Donnell) compared tenofovir levels in the blood of 29 out of the 30 people who became infected in the two PrEP arms with levels in a random selection of 198 people who did not become infected.
Tenofovir was undetectable in the blood of 70% of the people who became infected but only 18% of the people who did not, indicating a ‘true’ adherence level of about 80% – and having a detectable level of tenofovir in the blood was associated with an 86% reduction in HIV risk in those taking tenofovir and a 90% reduction in those on Truvada.
The FEM-PrEP study
In the FEM-PrEP study, 2056 HIV-negative women in South Africa, Kenya and Tanzania were randomised to take a daily Truvada pill or a placebo. The trial was stopped when an interim analysis found near-identical HIV infection rates in both trial arms. There were 33 HIV infections in women taking Truvada and 35 in women taking placebo; this translates into annual incidence rates of 4.7% and 5.0% respectively. This 0.3% difference is no difference at all, statistically speaking (hazard ratio 0.94, 95% confidence interval 0.59 to 1.52, p = 0.81).
Participants in the study said they took their pills 95% of the time and adherence as measured by pill count was 85%. However when drug levels of tenofovir and FTC were measured in the blood of women assigned to Truvada, the investigators found that less than 50% of the women who should have been taking the drug had actually done so in the last 12 days, and less than 40% within the last 48 hours.
In infected participants, 26% had detectable levels of tenofovir in their blood in the last visit before they tested HIV positive, 21% at the visit they tested positive, and 15% at both visits; in non-infected participants whose samples were taken at the same visits they were 35%, 38% and 26% respectively.
In FEM-PrEP, there were five cases of drug-resistant virus (all with the single M184V FTC resistance mutation), four in the Truvada arm and one on placebo. Two of the four cases in women assigned Truvada were clearly cases of transmission of virus that was already drug-resistant and not caused by women partially adherent to PrEP becoming infected, while the other two are still under investigation.
There were two cases of drug-resistant virus in Partners PrEP but in both cases these turned out to be people who were enrolled while suffering from acute HIV infection: there were no cases of drug-resistant virus amongst 74 infections post-randomisation.
One observation common to both studies was that the only side-effect that was measurably different between drug and placebo was nausea and vomiting. In Partners PrEP Truvada was associated with a modest increase in gastro-intestinal symptoms in the first month and in FEM-PrEP the rates were also significantly higher. Whether this is enough to deter participants from continuing their pills who are not strongly motivated needs further research.
Why were there differences in adherence?
Jared Baeten and Lut van Damme, principal investigators respectively of Partners PrEP and FEM-PrEP, were asked why they thought adherence was so much lower in FEM-PrEP than in Partners PrEP.
Baeten commented that they were very different populations. The men and women in Partners PrEP had to define themselves as being in a stable relationship – stable enough to last for at least the two-year length of the trial. Partners would have encouraged their spouse to take their pills, and a qualitative study has already confirmed that many participants saw PrEP as an opportunity to preserve their relationship despite the strain imposed by different HIV status.
He was asked why PrEP would be used in a couple where it would be more logical for the HIV-positive partner to be on treatment. He said one use of PrEP within couples might be to bridge the gap in time between the positive partner’s diagnosis and their starting treatment and becoming virally undetectable.
Van Damme said that the women in FEM-PrEP were much younger and had high levels of sexually transmitted infections (STIs). Initial qualitative surveys had shown that many did not believe themselves to be at high risk of HIV, despite high incidence in their community. There was also a high pregnancy rate in the study despite reported high levels of oral contraceptive use, showing that low adherence to medications was not restricted to Truvada. There was no evidence that participants were sharing their pills with others and, contrary to what the data initially suggested, the pregnancy rate was no higher in women taking PrEP, ruling out theories that interactions between the PrEP drugs and the menstrual cycle may have made women more vulnerable to HIV.
“What we have learned from this trial is that risk perception and understanding one’s own risk are important motivators for people to use biomedical prevention methods,” she concluded.
Dr Sharon Hillier of the Microbicides Trial Network, commenting on the PrEP trials at the conference, commented: “PrEP is very, very effective if you use it very, very well.”
Baeten J et al. ARV PrEP for HIV-1 prevention among heterosexual men and women. 19th Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 29, 2012. The abstract is available on the official conference website.
Van Damme L et al. The FEM-PrEP Trial of Emtricitabine/Tenofovir Disoproxil Fumarate (Truvada) among African Women. 19th Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 32LB, 2012. The abstract is available on the official conference website.
Donnell D et al. Tenofovir disoproxil fumarate drug levels indicate PrEP use is strongly correlated with HIV-1 protective effects: Kenya and Uganda. 19th Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 30, 2012. The abstract is available on the official conference website.
A webcast of the session HIV prevention: PrEP, microbicides and circumcision, is available through the official conference website.
Original Article via NAM
The kidneys are bean-shaped organs, about the size of an adult fist, located one on each side, around the middle of the back, just below the ribcage. Although most people have two kidneys, having one healthy kidney is enough to ensure that you remain well. Some treatments used in people with HIV have been associated with kidney problems and sometimes, HIV can cause a form of kidney disease.
Why talk about the Kidneys? – Well, it’s “World Kidney Day” – a joint initiative of the International Society of Nephrology (ISN) and the International Federation of Kidney Foundations (IFKF).
It’s mission is to raise awareness of the importance of our kidneys to our overall health and to reduce the frequency and impact of kidney disease and its associated health problems worldwide.
What do the Kidneys do?
The kidneys filter the blood and remove waste products from the normal breakdown of body tissue and from food. They regulate the body’s balance of minerals and water. Waste, excess minerals and water form urine, which flows to the bladder through tubes called ureters. The kidneys also release important hormones, notably one that stimulates the production of red blood cells (erythropoietin), and another that regulates blood pressure (renin). The kidneys also convert vitamin D into its active form, which is essential for healthy bones.
Common causes of kidney disease are inflammation in the filter, diabetes and high blood pressure. These may cause excessive loss of protein from the blood, blood in the urine, and/or chronic kidney failure. Infection in the urine can be limited to bladder (cystitis) or may affect the kidneys (pyelonephritis); some bacterial infections can reach the kidneys via the blood (tuberculosis). In acute kidney failure, the filtering process stops altogether; this can be caused if the blood supply to the kidneys is inadequate, with severe bacterial infections or with some substances that are toxic to the kidney. In diabetes, the excess glucose in the blood can damage the kidney blood vessels, causing a condition known as diabetic nephropathy. High blood pressure can damage the blood vessels. Drug toxicities most commonly damage the tubules.
Kidney problems in HIV infection
HIV itself can (uncommonly) cause a form of glomerulonephritis (HIV nephropathy). This inflammation of the kidneys is more often seen in black people and also in drug users. HIV nephropathy is probably less common with widespread use of anti-HIV drugs.
Diabetes is a possible side-effect of some anti-HIV drugs, particularly protease inhibitors. Drug toxicities, in people with HIV, may result from use of anti-HIV drugs or from drugs used to treat opportunistic infections (e.g. Septrin) or from some recreational drugs such as cocaine. The protease inhibitor Indinavir (Crixivan, now rarely used) can cause kidney stones. Stones are much more likely to form if you don’t drink enough liquid.
Tenofovir (Viread, also in the combination pills Truvada and Atripla) has been associated with a small number of cases of kidney problems.
Symptoms of kidney problems
Your kidney function and blood sugar should be monitored in your routine blood tests. Some kidney problems cause brown/red discolouration or frothy urine respectively. Excessive protein loss may cause fluid accumulation in the legs and elsewhere. An early sign that the kidneys are not working can be passing a lot of urine at night (also a symptom of diabetes).
The symptoms of more severe kidney failure may include a general feeling of malaise, tiredness, nausea, headaches, muscle cramps, reduced urine flow, drowsiness, itchy and, later, darkening of the skin. People with kidney stones caused by indinavir may notice severe pain in the flank (one side of the body), or a burning pain in the urethra when urinating. Urine infections can cause pain when urinating, frequency of urination, and especially if affecting the kidneys, also loin pain, fever and malaise.
Your kidney function will be checked as part of your routine HIV care.
Blood or protein in the urine can be detected by simple ‘stick’ tests; more detailed analysis can be done in a laboratory. Blood samples can be checked for mineral and protein levels, and for creatinine, which is a very sensitive and specific marker of kidney function, or urea, which is a less specific marker, being more affected by hydration and diet. Ultrasound, CT (computerised tomography) or MRI (magnetic resonance imaging) or functional scans can be used to image the kidneys. Some people may require renal biopsy, which involves taking a small sample of kidney tissue for examination under a microscope.
Changing treatment or reducing doses after talking to your doctor may be needed. If you are taking indinavir, drink at least two litres of water a day, more in hot weather or when exercising. Urinary infection should be treated promptly with appropriate antibiotics. Some forms of nephritis (inflammation of the kidneys) can be treated. If there is much protein loss and oedema (swelling), diuretics and a high protein diet may be used.
Raised blood sugar and blood pressure should be controlled carefully, the approach depending on the cause and severity of the problem. In moderate kidney failure, a low protein diet may help reduce symptoms and protect the kidneys; salt and potassium intake may need modification.
If your kidneys stop working completely, you would need dialysis (haemodialysis, which puts blood through an external filtering machine; or peritoneal dialysis, where fluid is put in and taken out of the abdominal cavity) to remove waste products and balance water and mineral levels; a kidney transplant, with immunosuppressive treatment to prevent it being rejected, may be needed if the kidneys have failed permanently, and good outcomes have been seen in people with HIV.
Original Article by Michael Carter at NAM
World Kidney day is a joint initiative of the International Society of Nephrology (ISN) and the International Federation of Kidney Foundations (IFKF).
The mission of World Kidney Day is to raise awareness of the importance of our kidneys to our overall health and to reduce the frequency and impact of kidney disease and its associated health problems worldwide.