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Wednesday 7 November 2018

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No increased risk of serious side-effects in PrEP users

Victoria Pilkington at HIV Glasgow 2018. Image credit: HIV Glasgow

A meta-analysis of randomised controlled trials of tenofovir or tenofovir/emtricitabine as pre-exposure prophylaxis (PrEP) has found no increase in the risk of serious adverse health events over placebo. In particular, the study showed no increase in bone fractures or significant kidney dysfunction, although mild kidney dysfunction (grades 1 and 2) occurred more frequently in PrEP users.

The meta-analysis was presented at the International Congress on Drug Therapy in HIV Infection (HIV Glasgow) by Victoria Pilkington of Imperial College, London.

Data was pooled from 13 placebo-controlled trials and one open-label study in which Truvada or tenofovir alone was compared to a placebo or no treatment. Three of the studies used tenofovir alone, one (IPERGAY) was of intermittent PrEP, and one (PROUD), compared Truvada versus no treatment.

The meta-analysis compared:

  • All serious or life-threatening adverse events (grade 3 and 4) on PrEP versus placebo.
  • All protocol-defined serious adverse events (i.e. ones the researchers had been expecting might happen) on PrEP versus placebo.
  • All grade 3 or 4 creatinine elevations on PrEP versus placebo.
  • All bone fractures on PrEP versus placebo.

The study found no significant difference between PrEP and placebo for any of these side-effects.

A subsequent analysis of grade 1 or 2 creatinine elevations – an early sign of reduced kidney function – showed a significantly greater number of events in people who took PrEP compared to placebo or no treatment (4.3% of PrEP users vs 2.3% of non-PrEP users).

The meta-analysis could not compare changes in bone mineral density or creatinine clearance due to inconsistent measurements between studies. The meta-analysis did not include acute side-effects such as nausea and headache.

Online purchases of generic PrEP

People buying generic PrEP (pre-exposure prophylaxis) online can be confident they are buying the real thing, according to research presented at the conference. Fourteen samples, including the generic products Tenvir-EM (Cipla) and Ricovir-EM (Mylan), were obtained from a range of suppliers. The samples were bought directly from online pharmacies and then tested by scientists at Imperial College London.

Branded Truvada contained 100% of the stated amounts of both drugs. The 13 generic samples contained between 97 and 104% of the claimed 200mg of emtricitabine and 94 to 105% of the stated amount of tenofovir. “We were able to confirm the stated content of PrEP tablets from various manufacturers and suppliers,” comment the investigators. “This study provides reassurance to the community purchasing generic PrEP online.”

Neural tube defects and integrase inhibitors

No further evidence of an increased risk of infant neural tube defects related to the use of dolutegravir or other integrase inhibitors in early pregnancy has emerged in safety reviews conducted over the past few months, researchers reported at the conference last week.

The potential risk of a harmful effect of the integrase inhibitor dolutegravir on foetal neurological development was flagged up after an increased incidence of neural tube defects was observed in the infants of mothers who had been taking dolutegravir at the time of conception in Botswana. The World Health Organization subsequently issued guidance to national treatment programmes which suggested that dolutegravir-based regimens should be avoided by women of childbearing potential unless they had adequate contraception in place.

Three cohorts reported on the incidence of neural tube defects in infants exposed to dolutegravir and other integrase inhibitors. The largest cohort, the Canadian Perinatal HIV Surveillance Program, found no retrospective reports of neural tube defects in 80 infants exposed to dolutegravir during the first trimester. However, the study did find a threefold higher rate of congenital abnormalities in infants exposed to elvitegravir during the first trimester.

The Frankfurt HIV Cohort found no cases of neural tube defects in 52 infants exposed to integrase inhibitors, while the Eastern and Central European Network Group found no cases in the infants of 28 women exposed to dolutegravir during pregnancy.

The investigators of the Eastern and Central European Network Group emphasised the importance of gathering data on other risk factors that may affect birth outcomes. In the dolutegravir-treated women, only 22 were taking folic acid supplements (which protect against neural tube defects), four were smoking prior to conception, three were using psychoactive substances and seven were using concomitant medication.

Glasgow HIV outbreak among people who inject drugs

Clinicians and nurse specialists from Glasgow provided an overview of how the city’s health services responded to an outbreak of rapid HIV transmission among people who inject drugs in the city after 2014.

The epidemic outbreak was concentrated among homeless drug users in the city, so staff from the Brownlee Centre for Infectious Diseases provided weekly clinics at the city’s homeless healthcare centre and conducted aggressive street outreach to ensure that once diagnosed with HIV, people who inject drugs remained engaged with clinical services. Antiretroviral drugs were dispensed alongside daily opioid substitution therapy at community pharmacies. People with hepatitis C and HIV co-infection could also be provided with direct-acting antiviral treatment for hepatitis C in the same setting.

Overall, 102 people who inject drugs diagnosed since 2014 have ever received antiretrovirals, reported Rebecca Metcalfe of the Brownlee Centre. Ninety-five per cent are currently on treatment and 86.5% of all those diagnosed have an undetectable viral load.

New antiretrovirals for treating people with multidrug-resistant HIV

Zvi Cohen at HIV Glasgow 2018. Image credit: HIV Glasgow

New data on two drugs recently developed for the treatment of people with extensive HIV drug resistance were presented at HIV Glasgow 2018.

Ibalizumab (Trogarzo) is a humanised monoclonal antibody that prevents HIV from using co-receptors after it attaches to a CD4 receptor. A treatment regimen containing ibalizumab led to substantial viral load reduction in a majority of highly treatment-experienced people with few treatment options left who received it, Dr Zvi Cohen of Theratechnologies reported at the conference.

After 48 weeks, 15 of 40 people who started treatment with ibalizumab had a viral load below 50 copies/ml on a regimen optimised by resistance testing. Participants were highly drug-resistant: at least 90% were resistant to one agent in the nucleoside reverse transcriptase inhibitor class, the non-nucleoside reverse transcriptase inhibitor class, and the protease inhibitor class and 68% were also resistant to at least one integrase inhibitor.

Ibalizumab (Trogarzo) was approved by the United States Food and Drug Administration in March 2018 for use in heavily treatment-experienced people with multidrug-resistant HIV failing on a current regimen. It is undergoing review by the European Medicines Agency.

Fostemsavir, another drug for the treatment of drug-resistant HIV, prevents HIV from attaching to CD4 cells by blocking a change in the shape of HIV’s gp120 protein that is necessary for the virus to engage with the CD4 receptor.

Results from the phase III BRIGHTE study showed that 54% of people who received fostemsavir in the randomised arm of the study and 38% in the open-label arm had an undetectable viral load after 48 weeks. All participants received a background regimen optimised by resistance testing. However, participants in the open-label arm had no active drugs available to form an optimised background regimen; participants in the randomised arm had one or two active drugs in at least two classes of antiretrovirals.

Fostemsavir is not yet licensed but ViiV Healthcare says that the drug will be developed for heavily treatment-experienced people.

Dolutegravir or lower-dose efavirenz equally effective

Eric Delaporte at HIV Glasgow 2018. Image credit: HIV Glasgow

Dolutegravir-based treatment was no more effective than treatment based on a 400mg dose of efavirenz, a randomised trial conducted in Cameroon has found. However, almost half of people with very high viral loads taking either regimen had a detectable viral load after 48 weeks, the results of the NAMSAL ANRS 12313 study showed.

Dolutegravir plus tenofovir and lamivudine is recommended as the preferred regimen for first-line antiretroviral treatment in low- and middle-income settings by the World Health Organization (WHO) in guidance issued in July 2018. This guidance recommended that dolutegravir should be used with reliable and consistent contraception by women of childbearing potential and that efavirenz 600mg could be used as an alternative, including when reliable contraception is not available.

Lowering the dose of efavirenz has benefits in terms of side-effects and cost. Efavirenz 400mg was recommended as an alternative option for first-line treatment by WHO in 2016 but there has been no head-to-head comparison with dolutegravir. This leaves national treatment programmes with a dilemma, for dolutegravir has been shown to be superior to efavirenz 600mg.

The study randomised 616 adults. The median CD4 cell count was 281 cells/mm3. Two-thirds of study participants had a high viral load (above 100,000 copies/ml) and a third had a viral load above 500,000 copies/ml.

After 48 weeks on treatment there was no significant difference in the proportion of participants in each arm who had a viral load below 50 copies/ml (74.5% in the dolutegravir arm and 69% in the efavirenz arm) but the study did find that both regimens were less effective at higher viral load levels. In participants with baseline viral loads above 500,000 copies/ml, 54.8% of the dolutegravir group and 57.9% of the efavirenz 400mg group had a viral load below 50 copies/ml at week 48.

None of those who experienced virologic failure on dolutegravir showed any evidence of drug resistance mutations but nine people who received efavirenz 400mg developed drug resistance, in three cases to all the drugs in the regimen.

Eric Delaporte of the University of Montpellier said that the findings supported the use of dolutegravir as a preferred first-line regimen, to preserve future treatment options.

Bictegravir matches dolutegravir in first-line treatment

Hans-Jürgen Stellbrink at HIV Glasgow 2018. Image credit: HIV Glasgow

A triple combination containing the new integrase inhibitor bictegravir proved just as effective as a dolutegravir-based combination in suppressing viral load over 96 weeks, but people taking bictegravir experienced significantly fewer adverse events, Professor Hans-Jürgen Stellbrink of the University of Hamburg reported at HIV Glasgow.

Bictegravir is a new integrase inhibitor. It has received regulatory approval in the European Union and the United States as part of a co-formulated, single-pill product called Biktarvy, combined with emtricitabine and tenofovir alafenamide.

The GS-1490 study presented at the conference compared Biktarvy to a regimen of dolutegravir, tenofovir alafenamide and emtricitabine in previously untreated people.

A primary endpoint analysis of the study was presented at the 9th International AIDS Society Conference on HIV Science in Paris in July 2017, showing no difference between the two regimens in rates of virological suppression after 48 weeks of treatment.

At HIV Glasgow, Hans-Jürgen Stellbrink presented results of the secondary endpoint analysis of the study: rates of virological suppression at 96 weeks and adverse events.

The intent-to-treat analysis, covering everyone randomised to participate in the study, showed that after 96 weeks, 84.1% of those receiving Biktarvy and 86.5% of those receiving dolutegravir-based treatment had a viral load below < 50 copies/ml, a non-significant difference.

Treatment-related adverse events were significantly more common in people receiving dolutegravir-based treatment than in the Biktarvy group (28% vs 20%, p = 0.02) but there was no difference in the rate of discontinuation due to adverse events (2%). The most common adverse events were nausea, diarrhoea and headache.

Hepatitis C increases the risk of premature delivery

Karolina Nowicka at HIV Glasgow 2018. Image credit: HIV Glasgow

Co-infection with hepatitis C greatly increases the risk of pre-term delivery for pregnant women with HIV, Karolina Nowicka of the Medical University of Warsaw told the conference. Co-infection was the only significant risk factor for pre-term delivery in 159 pregnancies between 2006 and 2017 in women receiving treatment at Warsaw’s HIV Out-patient Clinic. Women with hepatitis C and HIV co-infection were at least four times more likely to have a premature birth compared to women with HIV alone, she said.

Two-drug protease inhibitor treatment as effective as three-drug treatment

Zara Liew at HIV Glasgow 2018. Image credit: HIV Glasgow

Antiretroviral treatment with a boosted protease inhibitor and one other drug is just as effective as three-drug antiretroviral therapy containing a boosted protease inhibitor. Moreover, it results in fewer treatment discontinuations due to side-effects, a meta-analysis presented at the conference shows.

Treatment with a two-drug combination of generic antiretrovirals could significantly reduce the cost of treatment for previously untreated people and for people already virologically suppressed on a three-drug regimen. The meta-analysis found no difference in outcomes between people starting treatment and people switched from a three-drug regimen.

“Our results question why we are still using protease inhibitor three-drug regimens when two-drug regimens are as effective, as safe and cheaper,” said Zara Liew of Imperial College, London.

She pointed out that darunavir/ritonavir plus lamivudine has the potential to be much cheaper than either a three-drug regimen or a two-drug regimen containing dolutegravir.

Whereas dolutegravir/rilpivirine (Juluca) costs around £8500 a year in the United Kingdom and dolutegravir/lamivudine costs £6186 (based on the list price of the individual drugs), darunavir/ritonavir plus lamivudine costs £3942 a year and the cost may fall further as generic versions of darunavir/ritonavir become available over the next few years. In Argentina, for example, a generic version of darunavir/ritonavir costs less than £700 a year.

aidsmapLIVE: watch our AIDS 2018 Facebook panel discussion

Last week, NAM aidsmap hosted aidsmapLIVE, a Facebook panel discussion on the most important issues around HIV to come out of the 22nd International AIDS Conference (AIDS 2018).

The event is available to watch on Facebook.

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NAM's news reporting services from HIV Glasgow 2018 have been made possible thanks to support from Gilead Sciences, ViiV Healthcare and the organising committee of the HIV Glasgow conference.​

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