Waves—a randomized double-blind, placebo-controlled study—compared the impact of the following once-daily regimens in HIV-positive women who had not previously received treatment:

• Stribild – one pill that contains elvitegravir + cobicistat + tenofovir DF + FTC
• atazanavir (Reyataz) + ritonavir + tenofovir DF + FTC

After 48 weeks more women taking Stribild (87%) had an undetectable viral load (less than 50 copies/mL) compared to women taking the regimen based on atazanavir (81%). Side effects in this study were mainly related to harmless yellowing of the skin and whites of the eyes, which occurred among atazanavir users. This side effect caused more women (19) taking atazanavir to prematurely leave the study compared to the five women taking Stribild who left the study for other reasons. Stribild contains the integrase inhibitor elvitegravir. The Waves study underscores the general effectiveness and safety of elvitegravir-containing medicines in women and the leading position of integrase inhibitors in treatment guidelines.

Study details

In Waves, researchers enrolled women from the following countries:

• Belgium
• Dominican Republic
• France
• Italy
• Mexico
• Portugal
• Russia
• Thailand
• Uganda
• U.K.
• U.S.

The average profile of participants upon entering the study was as follows:

• age – 35 years
• main ethno-racial groups: black – 48%; white – 43%
• at least 75% of participants had symptom-free HIV infection
• HIV viral load – 32,000 copies/mL
• CD4+ cell count – 360 cells/mm³
• hepatitis B virus  co-infection – 4%
• hepatitis C virus co-infection – 8%
• eGFR (estimated glomerular filtration rate; an assessment of kidney health) – 106 mL/minute
• history of anxiety or depression – 20%
• use of tobacco – 25%
• use of alcohol – 50%
• use of street drugs – 3%

The average profile of women from the U.S. differed in a statistically significant manner from women outside the U.S. in the following ways:

History of anxiety or depression

• U.S. women – 53%
• non-U.S. women – 11%

Having a previous sexually transmitted infection

• U.S. women – 47%
• non-U.S. women – 30%

Recreational drug use

• U.S. women – 13%
• non-U.S. women – 1%

The study lasted for one year.

Results—Effectiveness

At the 48^th week of the study the distribution of participants on each regimen whose viral load was less than 50 copies/mL was as follows:

• Stribild – 87%
• atazanavir-based – 81%

Based on this difference, Stribild was judged to be statistically superior to the atazanavir-based regimen. However, bear in mind that part of the reason for Stribild’s apparent superiority (having more people on this regimen at week 48 with a suppressed viral load) is that a large fraction of women taking atazanavir dropped out of the study because of side effects.

Adverse events

The term adverse events refers to a range of unfortunate events that can happen during a clinical trial. Some of these events can be caused by the study medications, in other cases by an underlying illness or disease process or even by events (such as accidents) that may have nothing to do with the trial.

According to the researchers, most adverse events in the study were reported as “mild or moderate in severity.” More severe adverse events were distributed as follows:

• Stribild – 8%
• atazanavir-based regimen – 10%

No one died while in the study.

Discontinuations due to adverse events

The proportions of women who prematurely left the study due to adverse events were as follows:

• Stribild – 2%
• atazanavir-based – 7%

Reasons for prematurely leaving the study were as follows:

Stribild

• rash and nausea
• rash and yellowing of the skin
• elevated levels of liver enzymes in the blood
• indigestion
• stomach ulcer
• tuberculosis

Atazanavir-based regimen

• yellowing of the skin
• rash (in some cases this was severe or life-threatening)
• severe kidney injury
• decreasing eGFR

Focus on side effects

Side effects were distributed as follows:

Headache

• Stribild – 5%
• atazanavir-based regimen – 2%

Nausea

• Stribild – 11%
• atazanavir-based regimen – 10%

Vomiting

• Stribild – 5%
• atazanavir-based regimen – 3%

Diarrhea

• Stribild – 3%
• atazanavir-based regimen – 4%

Dizziness

• Stribild – 3%
• atazanavir-based regimen – 2%

Rash

• Stribild – 2%
• atazanavir-based regimen – 5%

Fatigue

• Stribild – 1%
• atazanavir-based regimen – 3%

Decreased appetite

• Stribild – 3%
• atazanavir-based regimen – 1%

Jaundice (yellowing of the skin)

• Stribild – 0%
• atazanavir-based regimen – 10%

Yellowing of the whites of the eyes (ocular icterus)

• Stribild – less than 1%
• atazanavir-based regimen – 12%

Focus on lab tests

Abnormal blood test results included the following:

Elevated levels of the liver enzyme ALT

• Stribild –1%
• atazanavir-based regimen – 2%

Elevated levels of the liver enzyme AST

• Stribild – 2%
• atazanavir-based regimen – 2%

Detectable sugar in the urine

• Stribild – 0%
• atazanavir-based regimen – 2%

In general, most abnormal blood test results were graded as mild or moderate in severity among women who used Stribild. In contrast, among women who used an atazanavir-based regimen, most abnormal blood test results were graded severe or very severe. This difference arose chiefly because of elevated levels of the waste product bilirubin. This effect is called hyperbilirubinemia and is a well-known side effect associated with atazanavir. In such cases, this elevated level of bilirubin in the blood is generally considered harmless and returns to normal when the person stops taking atazanavir.

There were no clinically significant differences in blood test results concerning cholesterol and triglycerides between people on the different study regimens.

Changes in eGFR associated with the study drugs were modest and similar between study regimens. This was also the case for differences in bone density.

Muscle and fat

One change that was significantly different between the two regimens was related to changes in the amount of muscle tissue. Women who used Stribild gained an average of 866 grams (almost two pounds) of muscle. In contrast, women who used an atazanavir-based regimen did not significantly gain any muscle but rather they gained 1.4 kg (about three pounds) of fat. Women who used Stribild did not gain significant amounts of fat.

Pregnancy

During the study 24 women became pregnant and 16 of them—eight taking Stribild and eight taking an atazanavir-based regimen—chose to continue taking the study drugs.

Miscarriages occurred in the first three months of the study among four women—two on each study regimen. As for the 12 remaining pregnant women in the study, their pregnancies and birthing process were uncomplicated and none of the babies had birth defects.

Key points

Both study regimens were generally safe and effective. However, Stribild was statistically superior to the regimen based on atazanavir. This statistical superiority was driven by the greater rate of discontinuations among women taking atazanavir who developed side effects. These side effects were mostly rash and elevated levels of bilirubin in the blood.

Rates of premature departure from the study were greater than previously reported in other trials of atazanavir-based regimens.

—Sean R. Hosein

REFERENCE:

Squires K, Kityo C, Hodder S, Johnson M, et al. Integrase inhibitor versus protease inhibitor–based regimen for HIV-1 infected women (WAVES): a randomised, controlled, double-blind, phase 3 study. Lancet HIV. 2016 Sep;3(9):e410-20.