HRQoL benefits and safety considerations with ART in people living with HIV

Cabotegravir (CAB) plus rilpivirine (RPV) is a long-acting (LA) injectable antiretroviral therapy (ART) recommended for people living with HIV (PLHIV) who have achieved viral suppression with oral medications. The health-related quality of life (HRQoL) impact of injectable CAB + RPV (Vocabria^®/ Rekambys^®, GlaxoSmithKline) and safety considerations of ART were discussed by experts in public health and patient advocates in an industry-sponsored satellite symposium during the 12^th International AIDS Society Conference on HIV Science (IAS 2023) held in Brisbane, Australia.

What is the “fourth 90”?
“A people-centred approach to HIV care advocated by the WHO focuses on three points: multimorbidity, stigma and discrimination, and QoL,” said Mr Nikos Dedes, Chair of Positive Voice, Athens, Greece.

The “three 90”, introduced as an additional goal by the Joint United Nations Programme on HIV/AIDS (UNAIDS), targets 90 percent of PLHIV knowing their HIV status, 90 percent of people who know their HIV status receiving ART, and 90 percent of people on HIV treatment having a suppressed viral load by 2020. [https://www.unaids.org/en/resources/909090] The new “fourth 90” target of ensuring that 90 percent of people with viral load suppression have good (ie, similar to that of the general population) HRQoL is intended to expand the continuum-of-services paradigm beyond the existing endpoint of viral suppression. [BMC Med 2016;14:94]

LA ART and HRQoL: Patients’ perspectives
Patient advocates shared their experience of HRQoL issues associated with earlier ART regimens and comorbidities.

“When I first started ART, I was taking 50–60 pills per day to cover HIV, prophylaxis, and comorbidities,” said Mr Jeff Taylor, a US patient advocate living with HIV for >40 years. “I have inherited gastroesophageal reflux disease [GERD], and when I was on oral RPV, managing it with carefully timed doses of antacids was becoming quite complex, so I was ready to switch to LA ART.”

Ms Bernadette Sharp, an Australian patient advocate and a woman living with HIV, said that the QoL benefits of LA ART make it one of the most exciting recent developments in the treatment landscape. “For years, I had to hide 2–4 months’ worth of oral ART medication in my home for fear that visitors who do not know my status might find out,” she shared. In addition to greater healthcare privacy, Sharp noted psychological benefits, treatment convenience and improved adherence with LA ART. “It’s nice not to be reminded of your status every day when you take a pill, and with LA ART it sometimes feels like you are not on treatment,” she elaborated. “When I was taking oral drugs, I would miss a dose a few times each month. I have a busy lifestyle and the 2-monthly dosing is convenient and can be combined with other regular health checks. I would not want to switch back to an oral regimen.”

Both Taylor and Sharp had experienced some injection site pain with LA ART, but this was effectively managed with aspirin or ibuprofen and decreased in intensity as they became accustomed to injectable therapy.

A survey of 688 PLHIV echoed the experience of patient advocates, with 83.3 percent of respondents perceiving a stigma from daily oral ART and 78.0 percent feeling stressed by the daily dosing schedule. [Sex Transm Infect 2021;97:566-573]

The same survey found that 65.8 percent of respondents were willing to try LA ART.“Injectable LA ARTs represent additional choice for both patients and healthcare providers and offer potential HRQoL benefits," said Dr Iskandar Azwa of Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia. These advantages stem from increased health privacy, reduction in stigma, avoidance of daily reminders of HIV, and convenience. [Curr Opin HIV AIDS 2022;17:127- 134; J Int Assoc Provid AIDS Care 2021;20:23259582211009011]

CARISEL was a multicentre, phase IIIb study, which assessed implementation effectiveness of switching to 2-monthly CAB + RPV injections after oral lead-in and initiation injections in 430 virologically suppressed PLHIV. The study found that implementation of LA ART in clinics was acceptable, appropriate and feasible. (Figure 1) [Open Forum Infect Dis 2022;doi:10.1093/ofid/ofac492.107]

“Unsurprisingly, almost all surveyed patients [99 percent; n=275/277] preferred LA ART to daily oral therapy,” commented Azwa. “Furthermore, there was only one instance of [confirmed] virological failure through 12 months of treatment.” (Figure 1)

Additional evidence regarding the impact of switching to LA ART on treatment satisfaction comes from SOLAR, a phase IIIb, randomized, open-label, multicentre, noninferiority study, which compared switching virologically suppressed adults (n=670) to CAB + RPV Q2M vs continuing bictegravir/emtricitabine/tenofovir alafenamide (B/FTC/TAF). [Ramgopal MN, et al, CROI 2023, abstract 191] In this study, improvements in treatment satisfaction scores from baseline (measured by the HIV Treatment Satisfaction Questionnaire score) at 12 months were significantly higher in the group switched to CAB + RPV vs patients who continued B/FTC/TAF (+3.36 vs -1.59; p<0.001).

“When LA ART became available, I was ready to switch, which made a difference to managing my other comorbidities,” shared Taylor.

RESPOND: Impact of INSTI- and TAF-related BMI changes on cardiometabolic risk
In PLHIV, use of integrase strand transfer inhibitors (INSTIs) and TAF is associated with increases in body mass index (BMI), while weight gain is associated with hypertension. [Lancet HIV 2021;8:e711-e722; EClinicalMedicine 2023;57:101836; Int J Infect Dis 2020;92:71-77] Since certain ART (eg, TAF) is associated with hypertension and dyslipidaemia, Australian guidelines recommend cardiovascular disease screening before initiating treatment. [Clin Drug Investig 2015;35:211-219; AIDS 2021;35:869-882; https://hivmanagement.ashm.org.au/ageing-with-hiv-infection/cardiovascular-disease-andassociated-risk-factors/]

“The clinical impact of treatment-associated weight gain is unclear,” noted Dr Dathan Byonanebye of Department of Community Health and Behavioural Sciences at Makerere University School of Public Health in Kampala, Uganda. To help fill this knowledge gap, the incidence of hypertension and dyslipidaemia in PLHIV receiving INSTI-based and/or TAF-based ART was compared with non-nucleoside reverse transcriptase inhibitors (NNRTIs) or boosted protease inhibitors (PIs) in the RESPOND consortium of HIV cohorts.

The RESPOND consortium comprises 19 observational cohorts of PLHIV in Europe and Australia, of which 13 were included in this analysis. Inclusion criteria for this analysis were age ≥18 years, no hypertension (blood pressure ≥140/90 mm Hg) or dyslipidaemia (total cholesterol >240 mg/dL, or HDL-cholesterol <35 mg/dL or triglycerides >200 mg/dL) at baseline, and use of INSTIs (dolutegravir, bictegravir, raltegravir, elvitegravir), boosted PIs (darunavir, atazanavir) or NNRTIs (efavirenz, rilpivirine). Patients were excluded if they were receiving non-ART associated with weight change. [HIV Med 2022;23:895-910; AIDS 2021;35:869-882; Byonanebye DM, et al, IAS 2023, abstract OALBB0505]

Of the 9,704 participants without hypertension, 2,977 (30.7 percent) developed hypertension over 39,993 person-years (PYs). In unadjusted estimates, hypertension was more common with INSTI with TAF or INSTI without TAF than ART without INSTI or TAF. Adjustment for time-updated BMI attenuated the risk with concurrent use of INSTI with TAF (adjusted incidence rate ratio [aIRR], 1.48; 95 percent confidence interval [CI], 1.31–1.68) or INSTI without TAF (aIRR, 1.25; 95 percent CI, 1.13–1.39). (Figure 2) This suggests some of the increased risk of hypertension could be due to BMI changes. At the same time, no interaction between ART and BMI was found (p=0.459). [Byonanebye DM, et al, IAS 2023, abstract OALBB0505]

Of the 5,231 participants included in the dyslipidaemia analysis, 2,689 (51.4 percent) developed events over 19,547 PYs. In unadjusted analysis, dyslipidaemia incidence was higher with concurrent use of TAF with INSTI or TAF alone. Adjustment for BMI attenuated dyslipidaemia risk associated with receiving TAF with INSTI (aIRR, 1.21; 95 percent CI, 1.07–1.37), while the risk associated with TAF alone became nonsignificant (aIRR, 1.15; 95 percent CI, 0.96–1.38). “These findings suggest that the interaction between BMI and dyslipidaemia is similar among ART types,” commented Byonanebye.

Overall, these data showed that current use of INSTI was associated with incident hypertension, and the risk remained significant despite attenuation after adjustment for time-updated BMI. TAF, but not INSTI, was associated with dyslipidaemia. The relationship between BMI and hypertension or dyslipidaemia did not differ among patients treated with INSTI or TAF, compared with those taking ART without INSTI or TAF. Byonanebye noted that these results may be limited by residual confounding (eg, missing data on family history of hypertension) and intraclass heterogeneity, but the large heterogenous cohort in RESPOND lends strength to the analysis.

LA CAB for HIV prevention
“The 2020s are a time of significant change in the therapeutic landscape for people living with or at risk of HIV,” said Dr Kristine Torjesen, Director of Science Facilitation at FHI 360. “New options at late stages of development include vaginal rings, new oral agents for preexposure prophylaxis [PrEP], and vaccines.” [https://avac.org/resource/infographic/years-ahead-in-hiv-preventionresearch-time-to-market-2/]

An important new option for PrEP that has already entered the market in some regions is CAB, administered as an intramuscular (IM) injection. “CAB injected every 2 months was found to be superior to TDF/FTC for preventing HIV infection in two clinical studies involving men who have sex with men and transgender women, and cisgender women,” explained Torjesen. [N Engl J Med 2021;385:595-608; Lancet 2022;399:1779-1789]

LA CAB for PrEP has already been approved by regulatory authorities in Australia, Botswana, Brazil, Malawi, South Africa, the US, and Zimbabwe. It is currently under going regulatory review in China, the EU, Malaysia, Philippines, Thailand, Vietnam, and other countries in Africa and South America. [https:// www.gsk.com/en-gb/media/press-releases/viiv-healthcare-s-cabotegravir-for-hiv-prevention-receivespositive-chmp-opinion-from-european-medicines-agency/] LA CAB is recommended by the WHO for people at substantial risk of HIV and is included on the WHO’s prequalified list for procurement by United Nations agencies. [https://www.who.int/news/item/28-07-2022-who-recommends-long-actingcabotegravir-for-hiv-prevention]