Sunlenca® (lenacapavir)
Efficacy Against HIV-2
Gilead Sciences, Inc. is providing this document to you, a US Healthcare Professional, in response to your unsolicited request for medical information.
Gilead Sciences, Inc. is providing this document to you, a US Healthcare Professional, in response to your unsolicited request for medical information.
Sunlenca® (lenacapavir)
Efficacy Against HIV-2
This document is in response to your request for information regarding the efficacy of Sunlenca® (lenacapavir [LEN]) as treatment for HIV-2.
Some data may be outside of the US FDA-approved prescribing information. In providing this data, Gilead Sciences, Inc. is not making any representation as to its clinical relevance or to the use of any Gilead product(s). For information about the approved conditions of use of any Gilead drug product, please consult the FDA-approved prescribing information.
The full indication, important safety information, and boxed warnings are available at:
www.gilead.com/-/media/files/pdfs/medicines/hiv/sunlenca/sunlenca_pi.
Product Labeling1
Indications and Usage
LEN, an HIV-1 capsid inhibitor, in combination with other ARV(s), is indicated for the treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug resistant HIV-1 whose current ARV regimen is failing due to resistance, intolerance, or safety considerations.
Microbiology
Antiviral activity in cell culture
LEN has antiviral activity that is specific to HIV (HIV-1 and HIV‑2). LEN was 15- to 25-fold less active against HIV-2 isolates relative to HIV-1.
Clinical Data on the Efficacy of LEN Against HIV-2
ANRS MIE CO5 HIV-2 Cohort (France)2
Study design and demographics
Efficacy of LEN against HIV-2 was evaluated in people with HIV-2 (N=8) who received treatment with LEN and an OBR in the French ANRS MIE CO5 HIV-2 Cohort. Outcomes included virologic response and changes in CD4 cell counts. Genotypic resistance testing was performed, and capsid sequences were compared to viral sequences obtained prior to LEN treatment to identify any mutations associated with treatment resistance. Phenotypic assays were also performed to assess drug susceptibility. OBR selection was determined using genotypic data; most participants received a backbone containing BIC, FTC, TAF, DTG, and DRV/R.
Table 1. Baseline Demographics and Disease Characteristics (Le Hingrat et al)2
Key Demographics and Characteristics | LEN + OBR |
Age, median (range), years | 57 (36–66) |
Male, n | 4 |
CD4, median (range), cells/mm3 | 135 (0–360) |
Resistance to all NRTIs, n | 3 |
Resistance to all NRTIs except zidovudine, n | 5 |
Resistance to all PIs, n | 7 |
Resistance to all INSTIs, n | 5 |
GSS of OBR, median (range) | 1.25 (0–2.5) |
≤1 fully active drug in OBR, n | 5 |
Abbreviations: INSTI=integrase strand transfer inhibitor.
Results
Most participants (6/8) had detectable HIV-2 VLs at initiation, with a median (range) of 3830 (665–60,400) c/mL. Two participants achieved virologic suppression (HIV-2 RNA <50 c/mL) after the OBR was initiated, which was a few weeks before LEN was initiated. Within 3 months of initiating LEN + OBR, 6 participants had ≥1 undetectable plasma VL. Of the 6 participants who had data available at Month 6, 3 participants had HIV-2 RNA <200 c/mL. Of these 3 participants, 1 had HIV-2 RNA <50 c/mL.
Data was available for 6 participants at Month 6; 1 participant achieved virologic suppression, and 3/6 participants had HIV-2 RNA <200 c/mL. The median (range) plasma VL among participants with HIV-2 RNA >50 c/mL was 757 (117–3000) c/mL. Within 1 year, HIV-2 RNA levels were near baseline levels.
From baseline to Month 6, the median (range) CD4 cell count for the 6 participants who had available data increased from 135 to 185 (90–290) cells/mm3, with a median gain of 3 (‑110 to +130) cells/mm3.
Capsid mutations were detected in 5 participants, with 1 virus selecting Q66H + R69 and 4 viruses presenting a N73D mutation, 2 of which were N73D + A76V. Three of these 4 participants had OBR GSS ≤1.5. Persistently high plasma VLs with no capsid mutations were observed in the remaining 3 participants. Phenotypic assay results found that the N73D mutation was associated with a 30-fold reduction in susceptibility to LEN (IC50 of N73D virus was 30-fold higher than IC50 of wild type).
No safety results were reported.
Case Report
There are limitations in the interpretation of case reports. Case reports cannot be generalized. Unlike controlled clinical trials, causality cannot be inferred based on uncontrolled observational data. In addition, incidence or prevalence cannot be estimated due to the lack of a representative population sample. Other limitations of case reports include the retrospective design and publication bias.3
An adult female patient presented with pneumonia and cytomegalovirus retinitis and tested positive for HIV-2 with a plasma VL of 1.2 × 104 c/mL in 2002. The patient was started on a combined ARV regimen of 3 NRTIs (3TC, TDF, and didanosine) but was unable to achieve virologic suppression. She was switched to an RTV-boosted PI + 2 NRTI regimen and achieved virologic suppression temporarily before experiencing virologic failure. After 5.6 years, the patient was switched to DRV/r + RAL + ABC/3TC, and virologic suppression was briefly achieved before virologic failure occurred. Two years later, RAL was discontinued, and the patient remained on DRV/r +ABC/3TC for approximately 4 years. The patient was then switched to DRV/c + DTG (initially 50 mg once daily and increased to 50 mg twice daily a couple years later) + ABC/3TC, which over the course of approximately 5 years was unable to lower HIV-2 plasma VL (2.2 × 104 c/mL) or improve CD4 T‑cell counts (90 cells/mcL), and T66I and G118R integrase substitutions emerged. LEN was then added on a compassionate use basis, with an oral lead-in followed by SUBQ LEN administration. The patient developed bursitis in her left hip in the months following the first injection, which was deemed unrelated to the administration of SUBQ LEN. The patient’s HIV‑2 plasma VL decreased to 115 c/mL, and CD4 counts increased to 260 cells/mcL; however, the N73D substitution in capsid emerged 41 days after LEN initiation. The patient was then switched to BIC/FTC/TAF + weekly oral LEN, resulting in modest decrease in her HIV-2 VL from 8.23 × 103 c/mL to 4.78 × 102 c/mL at the most recent VL assessment. CD4 T-cell counts maintained but did not improve significantly.4
In Vitro Data on Efficacy of LEN Against HIV-2
Kiarie et al5
Pseudovirion inhibition assays were used to assess the inhibition profile of LEN against HIV‑2 in cell culture. LEN inhibited HIV-2 (IC50 [SE]=206.2 [0.2] pM) and HIV-1 (IC50 [SE]=399.3 [±0.2]).
Smith et al6
The in vitro activity of LEN against HIV-2 was evaluated using HIV-1 and HIV-2 isolates from treatment-naive individuals. LEN activity against HIV-2 was significantly lower than HIV-1 (Figure 1), with the single-cycle and multicycle assays showing an 11- to 14-fold decrease, respectively. In single-cycle assay, LEN susceptibility was not affected by the presence of drug resistance mutations in HIV-2 reverse transcriptase, protease, or integrase (fold change in LEN [IC50]: 0.67–1 relative to wildtype HIVROD9), with the exception of a 1.9‑fold increase in the IC50 for the protease mutation 154M + I84V + L90M (P≤0.01). In multicycle assay, protease mutation 154M + I84V + L90M was fully susceptible to LEN.
Figure 1. Activity of LEN in HIV-1 vs HIV-2 Isolates (Smith et al)6
Link et al7
To determine susceptibility to LEN, 2 HIV-2 isolates (CBL20 and CDC310319) were analyzed in vitro by means of an antiviral assay using fresh human PBMCs. LEN demonstrated broad activity against these two HIV-2 clinical isolates (EC50: 885 pM; Figure 2).
Figure 2. Antiviral Activity of LEN Against HIV-2 (Link et al)7
Yant et al8
When human PBMCs were activated with PHA/IL-2 and infected with HIV-2 clinical isolates, LEN was found to be a suppressor of HIV-2 replication. High-resolution dose-response curves were used to determine EC50 and Hill slope values (Figure 3).
Figure 3. Antiviral Activity of LEN Against HIV-2 (Yant et al)8
References
1. SUNLENCA, Gilead Sciences Inc. SUNLENCA® (lenacapavir) tablets, for oral use. SUNLENCA® (lenacapavir) injection, for subcutaneous use. US Prescribing Information. Foster City, CA.
3. Nissen T, Wynn R. The Clinical Case Report: A Review of Its Merits and Limitations. BMC Res Notes. 2014;7:264. https://www.ncbi.nlm.nih.gov/pubmed/24758689
Abbreviations
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3TC=lamivudine
ABC=abacavir
ANRS MIE=National Agency for Research on AIDS and Viral Hepatitis
ARV=antiretroviral
BIC=bictegravir
CD4=cluster of differentiation-4
DRV=darunavir
DRV/c=darunavir/cobicistat
DRV/r=darunavir/ritonavir
DTG=dolutegravir
EC50=half maximal effective concentration
FTC=emtricitabine
GSS=genotypic susceptibility score
IC50=half maximal inhibitory concentration
IL-2=interleukin-2
LEN=lenacapavir
NRTI=nucleos(t)ide reverse transcriptase inhibitor
OBR=optimized background regimen
PBMC=peripheral blood mononuclear cell
PHA=phytohemagglutinin
PI=protease inhibitor
RAL=raltegravir
RTV=ritonavir
SUBQ=subcutaneous(ly)
TAF=tenofovir alafenamide
TDF=tenofovir disoproxil fumarate
VL=viral load
Product Label
For the full indication, important safety information, and boxed warning(s), please refer to the Sunlenca US Prescribing Information available at:
www.gilead.com/-/media/files/pdfs/medicines/hiv/sunlenca/sunlenca_pi.
Follow-Up
For any additional questions, please contact Gilead Medical Information at:
☎1‐866‐MEDI‐GSI (1‐866‐633‐4474) or www.askgileadmedical.com
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Please report all adverse events to:
Gilead Global Patient Safety ☎ 1-800-445-3235, option 3 or
www.gilead.com/utility/contact/report-an-adverse-event
FDA MedWatch Program by ☎ 1-800-FDA-1088 or MedWatch, FDA, 5600 Fishers Ln, Rockville, MD 20852 or www.accessdata.fda.gov/scripts/medwatch
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