Lipid Disorders Emerge as Key Focus in HIV Management at 2021 CROI Conference: Spotlight on Doravirine’s Metabolic Benefits

March 6-10, 2021 CROI (Conference on Retroviruses and Opportunistic Infections)Conference) held online. Comorbidities such as weight gain and dyslipidemia arising during long-term treatment of HIV-infected patients were widely discussed at the meeting.

 

The CROI conference is specifically designed for HIV and related fields.Basic ResearchAs a premier scientific exchange platform for researchers and clinicians, the annual Conference on Retroviruses and Opportunistic Infections (CROI), one of the most important industry conferences in the HIV field, attracts numerous leading authorities in HIV research.

 

 

Improving the quality of life for people living with HIV has always been a key focus of medical research. This year’s CROI conference presented multiple studies on the chronic disease burden associated with long-term treatment in this population, primarily focusing on cardiovascular risks andMetabolic Diseasesand other aspects.

 

Princy Kumar, Professor of Medicine and Microbiology and Director of the Division of Infectious Diseases at Georgetown University School of Medicine, presented a clinical study at the conference, which revealed that common comorbidities among people living with HIV includeHypertension, dyslipidemia, and neuropsychiatric disorders. Among them, the proportion of people living with HIV (PLWH) receiving antiretroviral therapy who developed three or more comorbidities was 37.2%, compared to 31.7% in the general population; the prevalence of dyslipidemia was 29.4% versus 24.6%.[1]

 

Another study on age-related non-AIDS comorbidities (NACM) also indicates that, compared with the generally healthy population, people living with HIV or those at risk of HIV infection, regardless of gender, have a higher prevalence and burden of NACM, includingHypertension, neuropsychiatric disorders, dyslipidemia, liver disease, and bone disease. EspeciallyHypertensionand dyslipidemia, occurring in individuals receiving long-term HIV treatmentHypertensionThe prevalence rates in men and women were 75% and 68%, respectively, while the prevalence of dyslipidemia was 64% in men and 41% in women.[2]

 

Both studies indicate that people living with HIV (PLWH) on long-term antiretroviral therapy (ART) are more prone to comorbidities such as hypertension and dyslipidemia. Therefore, physicians should prioritize the management of comorbidities in the long-term care of PLWH to mitigate the risk of their occurrence, which is crucial for improving the quality of life for this population.

 

A recent clinical study involving 4,577 HIV-infected individuals demonstrated that HIV patients receiving integrase inhibitor-containing regimens had a higher risk of developing dyslipidemia compared to those treated with non-nucleoside reverse transcriptase inhibitors (NNRTIs).[3]This further corroborates the advantages of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in improving lipid profiles among individuals living with HIV.

 

Taking doravirine (DOR), the next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) from MSD, as an example, the Phase III clinical trials DRIVE-AHEAD and DRIVE-FORWARD both demonstrated that, in addition to effective viral suppression, doravirine exhibited a favorable safety profile characterized by stable lipid levels, no weight gain, and a reduced risk of cardiovascular disease, thereby providing long-term benefits for people living with HIV.[4]

 

 

Figure 1. Results from the DRIVE-AHEAD 96-week study: Changes in fasting lipid profiles at 96 weeks in the doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF) group versus the efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) group. DOR/3TC/TDF reduced levels across all measured parameters, including low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol, and triglycerides. (Source: Clin Infect Dis, ciaa822, https://doi.org/10.1093/cid/ciaa822)

 

 

Figure 2. Results of the DRIVE-FORWARD Study at 96 Weeks: Changes in Fasting Lipid Levels Over 96 Weeks. Blue indicates the doravirine group, and orange indicates the DRV/r (darunavir/ritonavir) group. The doravirine group demonstrated superior control of low-density lipoprotein cholesterol (LDL cholesterol), non-high-density lipoprotein cholesterol (non-HDL cholesterol), and triglycerides. (Source: The Lancet HIV 2019 DOI:10.1016/S2352-3018(19)30336-4)

  

 

Integrase strand transfer inhibitor (INSTI)-based regimens have demonstrated superiority in terms of viral suppression, resistance profiles, and dosing convenience, thereby becoming the recommended first-line treatment in most countries worldwide. However, epidemiological data indicate a strong association between INSTI-based therapy and significant weight gain in people living with HIV. This weight gain-induced obesity is often a major contributor to dyslipidemia and the development of cardiovascular disease in this population.[5]

 

A study involving 7,770 individuals receiving antiretroviral therapy for HIStudies in HIV-infected individuals have shown that integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy regimens are associated with higher body mass index (BMI), increased risk of obesity, and greater waist circumference. Data indicate that the risk of obesity among HIV-infected individuals receiving INSTI-based antiretroviral therapy is 63% higher than that among those not receiving INSTI-containing regimens, with an average waist circumference 3.6 cm larger.[6]

 

BMI (Body Mass Index) is one of the important criteria for assessing obesity. At this year’s CROI conference, another study on integrase inhibitors showed that the combination regimen of TAF (tenofovir alafenamide fumarate) and DTG (dolutegravir) led to an increase in patients’ BMI by more than 7% compared with 3TC (lamivudine).[7]Furthermore, a comparative study based on DTG (dolutegravir) and NNRTIs (non-nucleoside reverse transcriptase inhibitors) also indicated that DTG-based regimens significantly increase body weight. Specifically, after 18 months of antiretroviral therapy, the estimated weight gain was 6.1 kg in women and 4.1 kg in men, which was substantially higher than that observed in people living with HIV receiving NNRTI-containing regimens (men: 3.6 kg increase; women: 2.8 kg increase).[8]

 

Therefore, when selecting antiretroviral therapy (ART) regimens for HIV, clinicians should consider the patient’s body weight to prevent drug-induced weight gain and subsequent obesity, thereby reducing the risk of cardiovascular diseases such as hypertension and hyperlipidemia in people living with HIV and alleviating their burden of chronic disease.

 

It is understood that doravirine is an innovative non-nucleoside reverse transcriptase inhibitor (NNRTI). Compared with integrase inhibitors and other NNRTIs, it does not affect body weight nor additionally cause dyslipidemia, thereby reducing the risk of cardiovascular disease in people living with HIV. In China, the doravirine monotherapy Pifeltro® and the fixed-dose combination Delstrigo® (doravirine/lamivudine/tenofovir disoproxil fumarate) were approved by the National Medical Products Administration in 2020 for the treatment of adult patients with no prior or current evidence of resistance to NNRTIs, lamivudine, or tenofovir.

 

At this year’s CROI conference, MSD also presented the latest data on doravirine and its investigational product, islatravir.

 

Notably, the combination of doravirine and islatravir for the treatment of HIV infection has further demonstrated its efficacy in viral suppression. Furthermore, data from the IMPAACT study indicate that the fixed-dose combination of doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF) exhibits a favorable safety and efficacy profile in adolescents with HIV. In adolescents aged 12–18 years weighing ≥45 kg, the pharmacokinetic profile of doravirine is consistent with that observed in adults. Overall virologic outcomes are also consistent with data reported in adult populations.[9] Striking data on the novel nucleoside reverse transcriptase translocation inhibitor (NRTTI) islatravir as a long-acting pre-exposure prophylaxis (PrEP) agent were also presented at the conference. MSD stated that it will further explore the potential of the islatravir subcutaneous implant as a long-acting PrEP regimen with up to 12 months of protection.

 

In the current era, where HIV/AIDS is managed as a chronic disease, attention must extend beyond the antiviral efficacy of medications to include issues such as weight gain and dyslipidemia. Addressing these factors is essential to further reduce the risk of cardiovascular disease during long-term disease management, thereby improving the quality of life for people living with HIV. The current intense discussion on lipid management represents a crucial step toward optimizing antiretroviral therapy. (Bioon)

References:

[1] COMORBIDITY BURDEN IN PEOPLE LIVING WITH HIV IN THE UNITED STATES _ Virtual Conference on Retroviruses and Opportunistic Infections 2021

[2] HIV DIFFERENTIALLY IMPACTS AGE-RELATED COMORBIDITY BURDEN AMONG US WOMEN AND MEN _ Virtual Conference on Retroviruses and Opportunistic Infections 2021

[3] Byonanebye DM; RESPOND Study Group. Incidence of dyslipidemia in people with HIV who are treated with integrase inhibitors versus other antiretroviral agents. AIDS. 2021 Jan 13. doi: 10.1097/QAD.0000000000002811. Epub ahead of print. PMID: 33443370.

[4] Molina JM, Squires K, Sax PE, Cahn P, Lombaard J, DeJesus E, Lai MT, Rodgers A, Lupinacci L, Kumar S, Sklar P, Hanna GJ, Hwang C, Martin EA; DRIVE-FORWARD trial group. Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 96-week results of a randomised, double-blind, non-inferiority, phase 3 trial. Lancet HIV. 2020 Jan;7(1):e16-e26. doi: 10.1016/S2352-3018(19)30336-4. Epub 2019 Nov 15. PMID: 31740348.

[5] Vekic J, Zeljkovic A, Stefanovic A, Jelic-Ivanovic Z, Spasojevic-Kalimanovska V. Obesity and dyslipidemia. Metabolism. 2019 Mar;92:71-81. doi: 10.1016/j.metabol.2018.11.005. Epub 2018 Nov 14. PMID: 30447223.

[6] ASSESSMENT OF OBESITY AND METABOLIC PROFILE BY INTEGRASE INHIBITOR USE IN REPRIEVE _ Virtual Conference on Retroviruses and Opportunistic Infections 2021 (002)

[7] ASSOCIATION BETWEEN NEWER ANTIRETROVIRALS AND INCREASE IN BODY MASS INDEX IN RESPOND _ Virtual Conference on Retroviruses and Opportunistic Infections 2021 (002)

[8] WEIGHT GAIN AMONG PARTICIPANTS STARTING DOLUTEGRAVIR-BASED HIV REGIMEN IN KENYA _ Virtual Conference on Retroviruses and Opportunistic Infections 2021 (002)

[9] IMPAACT 2014 24-WEEK PK AND SAFETY OF DORAVIRINE_3TC_TDF IN ADOLESCENTS WITH HIV-1 _ Virtual Conference on Retroviruses and Opportunistic Infections 2021 (002)