Treatment interruptions and viral control

One in nine people may be able to control their viral load after stopping HIV treatment, according to a new analysis. The researchers pooled data from 14 studies conducted since the year 2000.

Most of these were randomised controlled trials of interrupting antiretroviral therapy (this was investigated as a way of reducing the burden of HIV treatment a number of years ago, but was found to be unsafe). Some were studies of innovative forms of therapy, such as a therapeutic vaccination or immunological treatment, which required study participants to stop their conventional HIV treatment. A few were cohort studies of people treated in early HIV infection who then stopped their treatment, or of people already known to be viral controllers.

Among people who began HIV treatment very soon after infection and then stopped it, 13% achieved some degree of post-treatment viral control – in other words, they had a viral load below 400 copies/ml at least two-thirds of the time for at least 48 weeks after stopping HIV treatment. This group had been taking treatment for an average of two years. These findings are similar to those of a previous study, called VISCONTI, which found that 15% of people treated within six months of HIV infection might be post-treatment controllers.

The new analysis also looked for post-treatment controllers who did not start treatment so quickly. It found that 4% of people who had a treatment interruption after starting treatment in chronic infection (and taking it for an average of five years) had some degree of viral control. This is the first time a study has come up with an estimate for the proportion of people who start treatment in chronic HIV infection who may be post-treatment controllers.

The average duration of post-treatment viral control was a year and nine months. Three-quarters of people maintained viral control for more than a year, and 22% of them for at least five years.

However, the researchers’ definition of viral control was quite broad. A third of people described as having post-treatment viral control had at least one viral load measure above 1000 copies/ml, usually quite soon after treatment had been stopped. If the researchers had used a more strict definition – such as having a viral load under 400 copies/ml for at least 90% of the time – the proportion described as post-treatment controllers would only be 8% of early-treated and 2% of later-treated people.

Nonetheless, the researchers speculate that these short bursts of viral replication may actually contribute to the later viral suppression, at least in some people, as they may stimulate a suppressive anti-HIV immune response.

Dolutegravir monotherapy

Over the last few years, researchers have investigated ‘treatment simplification’ strategies to see whether a two-drug or one-drug HIV treatment can be safe and effective. Most of these studies have involved the use of the integrase inhibitor dolutegravir (Tivicay).

The two-drug strategy has proven to be effective for many people. This has been tested in combination with lamivudine, and also in combination with rilpivirine (Juluca is a two-drug combination pill containing dolutegravir and rilpivirine).

However, it is now clear that the one-drug strategy is unsafe. Using dolutegravir alone, as maintenance treatment after achieving undetectable viral load on a three-drug regimen, resulted in an unacceptable rate of viral rebound in a French study.

Although the results after 24 weeks of follow-up were encouraging, when the study was continued for 48 weeks, problems emerged. Seven of 78 people taking dolutegravir alone (monotherapy) saw their viral load rise to a detectable level. Two of them developed integrase inhibitor resistance mutations. If they had continued with their three-drug combination, rather than switching to dolutegravir monotherapy, this would be unlikely to have happened.

Experts now agree that dolutegravir monotherapy should not be used for initial treatment or as a simplification strategy for people who have previously been on standard HIV treatment.

Dolutegravir side-effects

What about the side-effects of dolutegravir? One reason that the drug is now so widely used (including as part of a conventional three-drug combination) is that it is thought to have fewer side-effects than efavirenz. However, in the last two years some clinicians have reported that neuropsychiatric side-effects such as insomnia, anxiety or depression have been occurring at much higher rates in people taking dolutegravir than clinical trials of the drug had indicated.

To investigate the incidence of discontinuation due to side-effects in a large population of patients, French researchers looked at 21,315 people who took integrase inhibitors between 2006 and 2016. They found that approximately one person in forty (2.7%) who started treatment with dolutegravir stopped taking the drug due to neuropsychiatric side-effects, a higher rate than seen in people taking either raltegravir (1.7%) or elvitegravir (1.3%).

The strength of this study is that it is based on a large cohort, from 18 different clinics in France, of people taking the drug in real-world conditions. The discontinuation rate is much lower than rates observed in the studies with smaller samples that drew people’s attention to this issue.

A separate analysis of five clinical trials of dolutegravir, sponsored by the drug’s manufacturer ViiV Healthcare, found that neuropsychiatric side-effects were more likely to occur in people with a prior history of psychiatric problems.

To find out more, read NAM’s factsheet on dolutegravir.

Diarrhoea

In recent clinical trials, an average of 17% of people living with HIV suffered from diarrhoea, a new study shows. Diarrhoea has multiple causes and only some of these cases are likely to be due to drug side-effects, but it’s a significant co-morbidity that affects people’s quality of life.

Diarrhoea in people with well-treated HIV usually has a non-infectious cause, such as drug side-effects or the effects of HIV on the gastrointestinal tract. The virus can infect the cells in the gastrointestinal tract and cause damage, especially to gut-associated immune system tissue. Such damage may not be repaired with HIV treatment and there is evidence that HIV continues to replicate in gut tissue despite an undetectable viral load. Another possible explanation is damage to autonomic nerves in the gastrointestinal tract.

Researchers pooled the results of 38 clinical trials of antiretroviral therapies conducted in the past decade, in the United States, with over 21,000 participants. The proportion of people with diarrhoea was 17% (including people who already had diarrhoea before beginning the trial). Diarrhoea was more commonly reported by people taking HIV treatment for the first time (20%) than for people who had previously taken treatment (14%).  

For more information, read NAM’s factsheet ‘Diarrhoea’.

Kidney disease and ethnicity

In the general population, as well as in people living with HIV, kidney disease is more common in black and Asian people, because of genetic factors. A new UK study shows that the risk of kidney disease varies according to the region of origin and is highest among those of west African descent.

The analysis included 7788 people living with HIV of black African or black Caribbean descent. During ten to 15 years of follow-up, 6% developed chronic kidney disease (a loss of kidney function that continues for a long period of time) and 2% developed end-stage kidney disease (a near-complete loss of kidney function, requiring dialysis or a transplant).

A gene called APOL1 raises the risk of kidney problems. Prevalence of this gene in sub-Saharan Africa is highest in west Africa, lower in southern Africa and lowest in east Africa. Many black Caribbean people are of west African ancestry and therefore have a similar genetic profile.

Consistent with this, the risk of kidney problems was lowest in people of east African ancestry. In comparison with them, the risk was three times higher in people from southern Africa, five times higher in people from the Caribbean and six times higher in people from west Africa.

A low CD4 cell count and an uncontrolled viral load were also risk factors for kidney disease.

For more information, read NAM’s factsheet ‘Chronic kidney disease and HIV’.

High blood pressure

High blood pressure is one of the most common health problems in people living with HIV, especially as people get older. Having high blood pressure (hypertension) raises the risk of heart disease and strokes.

Do anti-HIV drugs contribute to high blood pressure? A large study, following over 33,000 people for up to 14 years, has found no strong evidence that treatment with anti-HIV drugs significantly increases the risk of high blood pressure. The researchers collected data on 18 individual antiretroviral drugs as well as other risk factors.

High blood pressure was more common in men, older people, black African people, injecting drug users, people who’d previously had an AIDS diagnosis, as well as people who had diabetes, high blood lipids, lipodystrophy, obesity or kidney problems. Most of these risk factors are the same as in the general population.

The researchers say that their findings should provide reassurance that screening policies and preventative measures for high blood pressure used in the general population are also applicable for people with HIV.

To find out more, read NAM’s factsheet ‘High blood pressure’.