Background

People living with HIV are given medication to reduce (suppress) the amount of the virus in their blood called antiretroviral drugs (ARVs). Suppressing the virus results in improved immunity, reduction in sickness and reduced chances of transmission of the virus. However, these ARVs have to be taken for life to maintain suppression. However, in some cases, the first set of ARVs given may become ineffective in suppressing the virus necessitating a change to another option of drugs which is referred to as second line therapy. Just like any other medication, ARVs have side effects with some of the drugs used in second line therapy having more side effects than those used in the nationally recommended first-line therapy.

Over time, newer safer and easier to take ARVs have been made. The purpose of this study is to determine whether patients who are currently on the standard national second line therapy can be safely switched to a regimen containing one of the newer ARVs called dolutegravir. This is important because some studies have shown us that dolutegravir may achieve the same or better rates of viral suppression, may have less harmful effects to the body including improving cholesterol and may be simpler to take.

Dolutegravir is not a new drug, it has been used in this country for the last 4 years and is the recommended drug for first line HIV treatment (this is the very first regimen or HIV treatment one uses after a diagnosis of HIV).  It has not routinely been used for second line treatment in Kenya yet. Dolutegravir is a tablet that is swallowed. It can either be combined with other drugs in to one pill or be provided as a separate pill.

What questions are we trying to answer?

Sometimes we do not always know which drugs work best for different patients. To find out, we need to make comparisons between the different treatments. We put people into groups and give each group a different treatment; the results are compared to see if one is better. The areas we will assess at the end of this study are:

• Whether viral load will continue to be suppressed or will increase
• Change in CD4 count
• Change in lipid (cholesterol) levels
• Change in blood glucose
• Change in weight, body-mass index, waist-hip ratio and, waist circumference
• Whether any side effects are experienced
• How satisfied participants are with their treatment
• If the viral load is not suppressed, whether the virus develops any resistance

At the end of the study, we will determine whether these areas are equal in the study arms or whether one arm is better or worse than the other. This will help inform our knowledge and guidelines on management of second line antiretroviral therapy.

Where will the study be done?

This study will take place at Kenyatta National Hospital, Thika Level V Hospital, Kiambu County Hospital and Jaramogi Oginga Odinga Teaching and Referral Hospital.

How will the study be conducted?

Those currently on care at the study sites who are on second line treatment will be invited for a screening visit to review whether they can participate in the study. This will involve review of their medical history and laboratory tests. Those who are eligible for the study will either be given a new treatment combination containing dolutegravir or continue their treatment regimen without any change. For this study, the chances of being enrolled into one or the other arm is 1 in 2. To try to make sure the groups are the same to start with, each patient is put into a group by chance (randomly, this is what we call randomisation). 766 people living with HIV will be recruited in this study. Each participant will be followed up for up to 1 year, during which there will be at least five additional clinic visits on weeks 4, 12, 24, 36 and 48 from the enrollment visit. The results for the two groups will then compared. 

We expect that it will take about 18 months for all the 766 participants to go through 1 year of follow-up.

Background:  Kenya has the 4th largest HIV burden in the world with about 1.6 million people living with HIV.  Of these, just over 1 million are on antiretroviral therapy.  Current national guidelines recommend a first line regimen composed of 2 nucleoside reverse transcriptase inhibitors (NRTI) plus an integrase strand transfer inhibitor (INSTI) or a non-nucleoside reverse transcriptase inhibitor(NNRTI).  Second line regimens are composed of 2 NRTI plus a ritonavir boosted protease inhibitor(PIr).  This is based on evidence showing good clinical outcomes on this regimen.  Protease inhibitors are associated with multiple side effects including an increase is cardiovascular disease risk and, have significant drug to drug interactions that complicate management of other conditions such as tuberculosis.  INSTIs have been shown in one study to be an alternative to PIr in second line regimens when combined with fully active NRTIs.  It is not clear if this would still be the case if the activity of the NRTIs was not known.  We will evaluate the efficacy of switching from a PIr to a dolutegravir based second line ART regimen.

Hypothesis: switching virologically suppressed patients from a PIr based second line to a dolutegravir based second line is non-inferior to continuing on a PIr based second line.

Objectives: The primary objective will be to evaluate the non-inferiority of switching to a DTG containing regimen relative to maintaining a PI/r containing second-line regimen in virologically suppressed, INSTI-naive HIV-1 positive adults (≥ 18 years old) as determined by having HIV-1 RNA ≥ 50 copies/ml at week 48.  Secondary objectives will be to assess the impact of such a switch on CD4 counts, safety and tolerability.

Methods: Open-label, randomized, non-inferiority, multisite trial over 48 weeks, describing the efficacy and safety of switching from a second-line ARV regimen containing a ritonavir-boosted protease inhibitor (PI/r) plus 2 NRTIs to DTG plus 2 NRTIs in patients having achieved virological suppression (HIV-1 RNA < 50 copies/ml) for at least 12 weeks and with no prior INSTI exposure.  Adult consenting participants will be randomized at baseline to remain on their pre-enrollment PI/r or switch to DTG.  Participants will continue the NRTIs from their pre-enrollment regimen in both arms.  A total of 766 participants (388 in each arm) will be recruited from 4 sites - Kenyatta National Hospital, Kiambu County Hospital, Thika County Hospital and Jaramogi Oginga Odinga Teaching and Referral Hospital.

Conclusion: This study seeks to inform the guidelines around the efficacy and safety of alternative second line regimens.