Antiretroviral therapy switch to a dual regimen in an HIV-1–infected patient

Dr. Thomas Shiu-Hong Chik
Specialist in Infectious Disease
Hong Kong
15 Jun 2022
Antiretroviral therapy switch to a dual regimen in an HIV-1–infected patient

Presentation and investigations
A 40-year-old Chinese male security guard with good past health was referred for HIV testing in April 2019 since his male partner was found to be HIV-1 positive. Other than taking sleeping pills at times, the patient was not on any other medications. He was asymptomatic at the time of presentation.

Blood taking in April 2019 showed that his HIV-1 RNA level was 37,400 copies/mL and CD4 cell count was 273 cells/μL, which confirmed the diagnosis of chronic HIV-1 infection (Centers for Disease Control and Prevention [CDC] stage A2). Chest radiography showed no abnormalities and he also tested negative for hepatitis B virus (HBV) and hepatitis C virus. His complete blood count and renal function were normal, while alanaine transaminase (ALT) was mildly elevated at 70 IU/L and ultrasound revealed fatty liver. Additionally, the patient was obese (body weight, 92.7 kg; body mass index [BMI], 28.8 kg/m²). (Table)

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Treatment and response
Before starting antiretroviral therapy (ART), the patient underwent genotypic drug-resistance testing, which showed no major resistance. In April 2019, a four-drug single-tablet regimen (STR) comprising elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (EVG/COBI/FTC/TAF) QD was initiated, which resulted in improvement in CD4 cell count to 424 cells/μL in June 2019 and suppression of HIV viral loads to the undetectable level (<12.1 copies/mL) since October 2019. After 26 months of treatment with the four-drug regimen, the patient presented with significant increases in body weight (+18 kg) and BMI (from 28.8 kg/m² to 34.2 kg/m²) in June 2021. (Table) Although the patient did not control his diet, he claimed to have an active lifestyle without overeating.

Considering that the patient was already obese and experienced significant weight gain, ART was switched to a two-drug STR (2DR) of dolutegravir and lamivudine (DTG/3TC) QD in June 2021 after discussion with the patient.1 Two months after switching, his total cholesterol (TC) and triglyceride levels returned to normal ranges (TC, from 5.7 mmol/L to 5.0 mmol/L) (triglyceride, from 4.2 mmol/L to 1.2 mmol/L). Importantly, his CD4 cell count was 501 cells/μL and his HIV viral loads remained undetectable in August 2021.There was no treatment-emergent resistance to DTG/3TC. In September 2021, 3 months after switching, his body weight decreased by 7 kg, and his BMI decreased from 34.2 kg/m² to 32.1 kg/m². (Table)

Last seen in March 2022, the patient was on the 9th month of DTG/3TC treatment with good compliance. He was satisfied with treatment and experienced no adverse events. His latest HIV viral loads remained undetectable and his CD4 cell count remained satisfactory at 446 cells/μL.

Discussion
Physicians have long attempted to simplify ART regimens to reduce pill burden, improve adherence, and most importantly, minimize short and long-term toxicities in HIV-1–infected patients. Previously, ART was simplified by reducing the number of tablets or doses, which is best illustrated by the advent of STRs.2 However, given increasing rates of viral suppression achieved with highly active ART regimens, treatment can be simplified further by reducing the number of drugs.3,4

DTG/3TC is a 2DR indicated for treatment of HIV-1 infection in adults with no known or suspected resistance to the integrase inhibitor class, or to lamivudine (ie, antiretroviral-naïve adults and people with virologic suppression on a standard three- or four-drug regimen [3/4DR]).1 The efficacy of this 2DR in terms of maintenance of virologic suppression is supported by results of the pivotal TANGO trial.5 In this phase III, randomized, noninferiority study, 743 virologically suppressed (for >6 months) adults living with HIV-1 (male, 92.2 percent) who were taking a stable, first-line tenofovir alafenamide (TAF)based 3/4DR were randomized 1:1 to switch to DTG/3TC or to continue TAFbased 3/4DR through 144 weeks of therapy.5

In the primary analysis of TANGO at 48 weeks, switching to DTG/3TC vs continuing a TAF-based 3/4DR showed a noninferior virologic failure rate in the intention-to-treatexposed (ITT-E) population (adjusted treatment difference, -0.3 percent; 95 percent confidence interval [Cl], -1.20.7).5 At 144 weeks, 0.3 percent (1/369) of participants who switched to DTG/3TC vs 1.3 percent (5/372) of those who continued their TAF-based3/4DR had HIV-1 RNA 50 copies/mL, with noninferiority maintained with longer follow-up.6 Results of the 144-week per-protocol analysis favoured DTG/3TC in terms of a lower virologic failure rate vs continuation of TAF-based 3/4DRs (adjusted treatment difference, -1.1; 95 percent Cl, -2.3 to -0.0; p=0.04).6 Importantly, no resistance to DTG/3TC was observed in TANGO after up to 144 weeks (about 2.8 years) of follow-up.6

Consistent with TANGO results, our patient’s switch from EVG/COBI/FTC/TAF (a TAF-based regimen) to DTG/3TC did not result in virologic rebound. Throughout approximately 40 weeks of treatment with DTG/3TC, the patient’s HIV viral load remained undetectable, as in the majority of patients on DTG/3TC in TANGO.6 In addition, no resistance to DTG/3TC has emerged throughout the treatment period, confirming the high barrier to resistance of this 2DR.

While virologic suppression can be maintained with DTG/3TC, reducing the number of drugs to two from a 3/4DR may be important to reduce drug toxicity.6 For example, both second-generation integrase strand transfer inhibitors (INSTIs) and TAF have been implicated in weight gain during treatment, and if weight is a concern, it is not advisable to switch to a regimen containing both. In such situations, a nucleoside reverse transcriptase inhibitor (NRTI)reducing strategy may be an option while keeping the patient on an INSTI.7

In TANGO, switching to DTG/3TC instead of continuing a TAF-based 3/4DR was associated with greater decreases from baseline in TC (-3.3 percent vs +4.2 percent; p<0.001), HDL-cholesterol (-2.4 percent vs +3.9 percent; p<0.001), LDL-cholesterol (-3.0 percent vs +4.6 percent; p<0.001), and triglycerides (-9.7 percent vs +2.2 percent; p=0.001) at week 144, showing a lipid profile favouring DTG/3TC.6,8 (Figure)

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Our patient suffered from significant weight gain (+18 kg in 26 months) after initiating EVG/COBI/FTC/TAF, which was likely attributable to the elvitegravir and TAF components.7 Adopting an NRTI-reducing strategy resulted in weight loss while the patient was on an INSTI (DTG) and an NRTI (3TC) the integral components of complete ART. At the same time, the patient’s TC decreased by 7.5 percent and triglycerides decreased by 87 percent, which exceeded the average changes observed in the DTG/3TC arm in TANGO. The profound reduction in triglycerides in our patient was in line with TANGO findings.6

TANGO was conducted in a predominantly male population, while the recently published SALSA trial investigated the performance of DTG/3TC in more diverse patient groups (female, 39 percent; Asian, 14 percent).6,9 SALSA did not restrict the NRTI backbone used at baseline. At week 48, switching to DTG/3TC was shown to be noninferior to continuing CARs (HIV-1 RNA 50 copies/mL [FDA Snapshot], 0.4 percent vs 1.2 percent; 95 percent Cl, -2.40.8).9

Both TANGO and SALSA concluded that adopting an NRTI-reducing strategy by switching to DTG/3TC was efficacious in maintaining long-term virologic suppression. TANGO provided results of nearly 3 years of follow-up, while SALSA was conducted in a broader population.6,9

Building on these results, DTG/3TC is a possible switch option for patients already on two NRTIs. For example, continued use of abacavir may not be advisable in patients with heightened cardiovascular risk. On the other hand, those with renal impairment or Fanconi syndrome, and those with osteopaenia or osteoporosis, are not good candidates for continuing a TDF-based regimen. In such cases, the use of an NRTI-reducing 2DR such as DTG/3TC may be viable.

Suitable candidates for treatment switch to the DTG/3TC regimen are patients with good drug compliance, no pre-existing resistance to the drug components, HBV-negative status, and a viral load <500,000 copies/mL, such as our patient.

To conclude, our case and clinical trials demonstrate that the NRTI-reducing strategy would not compromise virologic suppression, and may help reduce drug toxicity (ie, weight gain and changes in lipid parameters) that can be cumulative in the long term.

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